Isoquinolinesulfonyl derivatives

ABSTRACT

A 5-isoquinolinesulfonyl derivative of Formula (I): ##STR1## wherein l is zero or one; 
     m and n each is an integer of one to nine; 
     m+n is an integer of at least one 
     R 1  is a hydrogen atom, a C 1-10  alkyl group, a C 5-6  cycloalkyl group or an aryl group; or 
     R 2  and R 3  each is a hydrogen atom, a C 1-10  alkyl group, a C 5-6  cycloalkyl group, an aryl group or an aralkyl group; 
     R 2  and R 3  are C 1-6  alkylene groups and linked directly or through an oxygen atom to form a 5- to 7-membered heterocyclic ring with the adjacent nitrogen atom; or 
     the ##STR2##  group is a ##STR3##  group wherein R 4  and R 5  each is a hydrogen atom, a C 1-10  alkyl group, an aryl group or an aralkyl group and R 6  is a hydrogen atom, a C 1-10  alkyl group, an aryl group, an aralkyl group, a benzoyl group, a cinnamyl group, a cinnamoyl group, a furoyl group or a ##STR4##  group wherein R 7  is a C 1-8  alkyl group; and the pharmaceutically acceptable salt thereof; and a process for the preparation thereof. The compounds of this invention have a relaxatory action for vascular smooth muscle and are useful as a vasodilator and a hypotensor.

This is a division of application Ser. No. 357,770, filed Mar. 12, 1982, now U.S. Pat. No. 4,456,757.

BACKGROUND OF THE INVENTION Field of the Invention

This invention relates to novel isoquinolinesulfonyl derivatives which possess a relaxatory action for vascular smooth muscle and are useful as a vasodilator and a hypotensor, and a process for the preparation thereof.

SUMMARY OF THE INVENTION

According to the present invention in one embodiment there is provided an isoquinoline derivative of Formula (I): ##STR5## wherein

l is zero or one;

m and n each is zero or an integer of one to nine;

m+n is an integer of at least one;

R₁ is a hydrogen atom, a C₁₋₁₀ alkyl group, a C₅₋₆ cycloalkyl group or an aryl group;

R₂ and R₃ each is a hydrogen atom, a C₁₋₁₀ alkyl group, a C₅₋₆ cycloalkyl group, an aryl group or an aralkyl group;

R₂ and R₃ may be C₁₋₆ alkylene groups and linked directly or through an oxygen atom to form a 5- to 7-membered heterocyclic ring with the adjacent nitrogen atom; or

the ##STR6## group is a ##STR7## group wherein R₄ and R₅ each is a hydrogen atom, a C₁₋₁₀ alkyl group, an aryl group or an aralkyl group and R₆ is a hydrogen atom, a C₁₋₁₀ alkyl group, an aryl group, an aralkyl group, a benzoyl group, a cinnamyl group, a cinnamoyl group, a furoyl group or a ##STR8## group wherein R₇ is a C₁₋₈ alkyl group; and the pharmaceutically acceptable acid addition salt thereof.

The present invention in another embodiment provides a process of preparing th above described isoquinolinesulfonyl derivative.

DETAILED DESCRIPTION OF THE INVENTION

Exemplary R₁ groups in Formula (I) include a hydrogen atom; C₁₋₁₀ alkyl groups, preferably C₁₋₆ alkyl groups, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl and decyl; C₅₋₆ cycloalkyl groups such as cyclopentyl and cyclohexyl; and aryl groups such as phenyl. The R₂ and R₃ groups in Formula (I) may be the same or different and exemplary R₂ and R₃ groups include a hydrogen atom; C₁₋₁₀ alkyl groups, preferably C₁₋₈ alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl and n-decyl; C₅₋₆ cycloalkyl groups such as cyclopentyl and cyclohexyl; aryl groups such as phenyl; and aralkyl groups such as benzyl. Exemplary 5- to 7-membered heterocyclic rings formed by linking R₂ and R₃ directly or through an oxygen atom together with the adjacent nitrogen atom include 1-pyrrolidinyl, piperidino, homopiperidino and morpholino groups. Preferred ##STR9## groups include amino, methylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino, isobutylamino, n-hexylamino, cyclohexylamino, dimethylamino, diethylamino, di-n-butylamino, N-methyl-N-cyclopentylamino, N-methyl-N-cyclohexylamino, N-methyl-N-phenylamino, N-methyl-N-benzylamino, N-ethyl-N-benzylamino, N-isopropyl-N-benzylamino, 1-pyrrolidinyl, piperidino, homopiperidino and morpholino groups. The ##STR10## group may also be a ##STR11## group. The R₂ and R₃ groups may be the same or different and exemplary R₄ and R₅ groups include a hydrogen atom; C₁₋₁₀ alkyl groups, preferably C₁₋₆ alkyl groups, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-pentyl, isopentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl and n-decyl; C₅₋₆ cycloalkyl groups such as cyclopentyl and cyclohexyl; aryl group such as phenyl; and aralkyl groups such as benzyl, α-phenethyl and β-phenethyl. Exemplary R₆ groups include a hydrogen atom; C₁₋₁₀ alkyl groups, preferably C₁₋₆ alkyl groups, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-pentyl, isopentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl and n-decyl; aryl groups such as phenyl; aralkyl groups such as benzyl, α-phenethyl and β-phenethyl; a benzoyl group; a cinnamyl group; a cinnamoyl group; a furoyl group; a ##STR12## group wherein R₇ is a C₁₋₈ alkyl group, preferably a C₁₋₄ alkyl group, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-pentyl, n-hexyl, n-heptyl and n-octyl groups. Preferred ##STR13## groups include piperazino, 2-methylpiperazino, 2-ethylpiperazino, 3-ethylpiperazino, 3-isopropylpiperazino, 3-isobutylpiperazino, 2-phenylpiperazino, 3-phenylpiperazino, 3-benzylpiperazino, 2,3-dimethylpiperazino, 2,5-dimethylpiperazino, 3,5-dimethylpiperazino, 2,6-dimethylpiperazino, 2-methyl-5-ethylpiperazino, 2-methyl-5-n-propylpiperazino, 2-methyl-5-isopropylpiperazino, 2-methyl-5-isobutylpiperazino, 2-methyl-5-phenylpiperazino, 2-methyl-5-benzylpiperazino, 2,5-diethylpiperazino, 2-ethyl-5-n-butylpiperazino, 4-methylpiperazino, 4-ethylpiperazino, 4-n-propylpiperazino, 4-isobutylpiperazino, 4-n-hexylpiperazino, 4-phenylpiperazino, 4-benzylpiperazino, 4-phenethylpiperazino, 4-benzoylpiperazino, 4-cinnamylpiperazino, 4-cinnamoylpiperazino, 4-furoylpiperazino, 4-(2-methoxy-2-phenethyl)piperazino and 4-(2-ethoxy-2-phenethyl)piperazino groups.

Preferred embodiments are as follows:

(a) A compound of Formula (XIII) ##STR14## wherein

R₂ and R₃ each is a hydrogen atom, a C₁₋₈ alkyl group, a phenyl group or a benzyl group, and when one of R₂ and R₃ is a hydrogen atom, the other is not a hydrogen atom; or

R₂ and R₃ are C₁₋₆ alkylene groups and linked directly or through an oxygen atom to form a 5- to 7-membered heterocyclic ring together with the adjacent nitrogen atom; or

the ##STR15## group is a ##STR16## group wherein R₄ and R₅ each is a hydrogen atom, a C₁₋₆ alkyl group, a phenyl group or a benzyl group and R₆ is a hydrogen atom, a C₁₋₆ alkyl group, a phenyl group, a benzyl group, a phenethyl group, a benzoyl group, a cinnamyl group, a cinnamoyl group, a furoyl group or a ##STR17## group wherein R₇ is a C₁₋₄ alkyl group; and pharmaceutically acceptable acid addition salts thereof, i.e., a compound of Formula (I) wherein l is zero.

(b) The compound of (a), wherein R₂ is a hydrogen atom or a C₁₋₆ alkyl group and R₃ is a C₁₋₆ alkyl group.

(c) The compound of (a), wherein the ##STR18## group is a 1-pyrrolidinyl group, a piperidino group or a morpholino group.

(d) The compound of (a), wherein the ##STR19## group is a ##STR20## group wherein R₆ is a hydrogen atom and R₄ and R₅ each is a hydrogen atom, a C₁₋₆ alkyl group, a phenyl group or a benzyl group.

(e) The compound of (d), wherein R₆, R₄ and R₅ are hydrogen atoms.

(f) The compound of (d), wherein R₄ is a hydrogen atom or a C₁₋₆ alkyl group and R₅ is a C₁₋₆ alkyl group, a phenyl group or a benzyl group.

(g) The compound of (a), wherein the ##STR21## group is a ##STR22## group wherein R₄ and R₅ are hydrogen atoms and R₆ is a C₁₋₆ alkyl group, a phenyl group, a benzyl group, a phenethyl group, a benzoyl group, a cinnamyl group, a cinnamoyl group, a furoyl group or a ##STR23## group wherein R₇ is a C₁₋₄ alkyl group.

(h) The compound of (g), wherein R₆ is a C₁₋₆ alkyl group.

(i) The compound of (g), wherein R₆ is a phenyl group, a benzyl group, a phenethyl group, a benzoyl group, a cinnamyl group, a cinnamoyl group or a furoyl group.

(j) The compound of (g), wherein R₆ is a ##STR24## group wherein R₇ is a C₁₋₄ alkyl group.

(k) A compound of Formula (XIV): ##STR25## wherein

m and n each is zero or an integer of one to nine;

m+n is an integer of one to nine;

R₁ is a hydrogen atom, a C₁₋₆ alkyl group or a phenyl group;

R₂ and R₃ each is a hydrogen atom, a C₁₋₈ alkyl group, a C₅₋₆ cycloalkyl group, a phenyl group or a benzyl group; or

R₂ and R₃ are C₁₋₆ alkylene groups and linked directly or through an oxygen atom to form a 5- to 7-membered heterocyclic ring together with the adjacent nitrogen atom; or

the ##STR26## group is a ##STR27## group wherein R₄ and R₅ each is a hydrogen atom, a C₁₋₆ alkyl group, a phenyl group or a benzyl group and R₆ is a hydrogen atom, a C₁₋₆ alkyl group, a phenyl group, a benzyl group, a phenethyl group, a benzoyl group, a cinnamyl group, a cinnamoyl group, a furoyl group or a ##STR28## group wherein R₇ is a C₁₋₄ alkyl group; and pharmaceutically acceptable acid addition salts thereof, i.e., a compound of Formula (I), wherein l is one.

(l) The compound of (k), wherein m and n each is zero or an integer of one to nine, m+n is an integer of one to nine and R₁, R₂ and R₃ are hydrogen atoms.

(m) The compound of (k), wherein m and n each is zero or one, m+n is one, R₂ and R₃ are hydrogen atoms and R₁ is a C₁₋₆ alkyl group or a phenyl group.

(n) The compound of (k), wherein m and n each is zero or an integer of one to two, m+n is one or two, R₁ is a hydrogen atom, R₂ is a hydrogen atom or a C₁₋₄ alkyl group and R₃ is a C₁₋₆ alkyl group, a C₅₋₆ cycloalkyl group, a phenyl group or a benzyl group.

(o) The compound of (k), wherein m and n each is zero or an integer of one to two, m+n is one or two, R₁ is a hydrogen atom and R₂ and R₃ form together with the adjacent nitrogen atom a piperidino group or a morpholino group.

Exemplary isoquinolinesulfonyl derivatives of this invention include:

(1) N-(2-aminoethyl)-5-isoquinolinesulfonamide referred to as "Compound (1)";

(2) N-(3-aminopropyl)-5-isoquinolinesulfonamide referred to as "Compound (2)";

(3) N-(4-aminobutyl)-5-isoquinolinesulfonamide referred to as "Compound (3)";

(4) N-(6-aminohexyl)-5-isoquinolinesulfonamide referred to as "Compound (4)";

(5) N-(10-aminodecyl)-5-isoquinolinesulfonamide referred to as "Compound (5)";

(6) N-(2-amino-1-methylethyl)-5-isoquinolinesulfonamide referred to as "Compound (6)";

(7) N-(1-aminomethylpropyl)-5-isoquinolinesulfonamide referred to as "Compound (7)";

(8) N-(1-aminomethylpentyl)-5-isoquinolinesulfonamide referred to as "Compound (8)";

(9) N-(2-aminopropyl)-5-isoquinolinesulfonamide referred to as "Compound (9)";

(10) N-(2-aminobutyl)-5-isoquinolinesulfonamide referred to as "Compound (10)";

(11) N-(2-amino-3-methylbutyl)-5-isoquinolinesulfonamide referred to as "Compound (11)";

(12) N-(2-amino-1-phenylethyl)-5-isoquinolinesulfonamide referred to as "Compound (12)";

(13) N-(2-amino-2-phenylethyl)-5-isoquinolinesulfonamide referred to as "Compound (13)";

(14) N-(2-methylaminoethyl)-5-isoquinolinesulfonamide referred to as "Compound (14)";

(15) N-(2-ethylaminoethyl)-5-isoqinolinesulfonamide referred to as "Compound (15)";

(16) N-(2-isopropylaminoethyl)-5-isoquinolinesulfonamide referred to as "Compound (16)";

(17) N-(3-dimethylaminopropyl)-5-isoquinolinesulfonamide referred to as "Compound (17)";

(18) N-(3-diethylaminopropyl)-5-isoquinolinesulfonamide referred to as "Compound (18)";

(19) N-(3-di-n-butylaminopropyl)-5-isoquinolinesulfonamide referred to as "Compound (19)";

(20) N-(3-piperidinopropyl)-5-isoquinolinesulfonamide referred to as "Compound (20)";

(21) N-(3-morpholinopropyl)-5-isoquinolinesulfonamide referred to as "Compound (21)";

(22) N-[3-(N-methyl-N-cyclohexylamino)propyl]-5-isoquinolinesulfonamide referred to as "Compound (22)";

(23) N-[3-(N-methyl-N-phenylamino)propyl]-5-isoquinolinesulfonamide referred to as "Compound (23)";

(24) N-[3-(N-methyl-N-benzylamino)propyl]-5-isoquinolinesulfonamide referred to as "Compound (24)";

(25) N-methyl-5-isoquinolinesulfonamide referred to as "Compound (25)";

(26) N-ethyl-5-isoquinolinesulfonamide referred to as "Compound (26)";

(27) N-n-Butyl-5-isoquinolinesulfonamide referred to as "Compound (27)";

(28) N-isobutyl-5-isoquinolinesulfonamide referred to as "Compound (28)";

(29) N,N-dimethyl-5-isoquinolinesulfonamide referred to as "Compound (29)";

(30) N,N-diethyl-5-isoquinolinesulfonamide referred to as "Compound (30)";

(31) N,N-di-n-butyl-5-isoquinolinesulfonamide referred to as "Compound (31)";

(32) 1-(5-isoquinolinesulfonyl)piperidine referred to as "Compound (32)";

(33) 4-(5-isoquinolinesulfonyl)pyrrolidine referred to as "Compound (33)";

(34) 1-(5-isoquinolinesulfonyl)morpholine referred to as "Compound (34)";

(35) 1-(5-isoquinolinesulfonyl)piperazine referred to as "Compound (35)";

(36) 1-(5-isoquinolinesulfonyl)-4-methylpiperazine referred to as "Compound (36)";

(37) 1-(5-isoquinolinesulfonyl)-3-methylpiperazine referred to as "Compound (37)";

(38) 1-(5-isoquinolinesulfonyl)-2-methylpiperazine referred to as "Compound (38)";

(39) 1-(5-isoquinolinesulfonyl)-3,5-dimethylpiperazine referred to as "Compound (39)";

(40) 1-(5-isoquinolinesulfonyl)-2,5-dimethylpiperazine referred to as "Compound (40)";

(41) 1-(5-isoquinolinesulfonyl)-2,3-dimethylpiperazine referred to as "Compound (41)";

(42) 1-(5-isoquinolinesulfonyl)-4-ethylpiperazine referred to as "Compound (42)";

(43) 1-(5-isoquinolinesulfonyl)-3-ethylpiperazine referred to as "Compound (43)";

(44) 1-(5-isoquinolinesulfonyl)-4-n-propylpiperazine referred to as "Compound (44)";

(45) 1-(5-isoquinolinesulfonyl)-3-isopropylpiperazine referred to as "Compound (45)";

(46) 1-(5-isoquinolinesulfonyl)-3-isobutylpiperazine referred to as "Compound (46)";

(47) 1-(5-isoquinolinesulfonyl)-4-isobutylpiperazine referred to as "Compound (47)";

(48) 1-(5-isoquinolinesulfonyl)-2,5-diethylpiperazine referred to as "Compound (48)";

(49) 1-(5-isoquinolinesulfonyl)-2-methyl-5-isobutylpiperazine referred to as "Compound (49)";

(50) 1-(5-isoquinolinesulfonyl)-2-methyl-5-benzylpiperazine referred to as "Compound (50)";

(51) 1-(5-isoquinolinesulfonyl)-4-hexylpiperazine referred to as "Compound (51)";

(52) 1-(5-isoquinolinesulfonyl)-2-phenylpiperazine referred to as "Compound (52)";

(53) 1-(5-isoquinolinesulfonyl)-3-phenylpiperazine referred to as "Compound (53)";

(54) 1-(5-isoquinolinesulfonyl)-3-benzylpiperazine referred to as "Compound (54)";

(55) 1-(5-isoquinolinesulfonyl)-4-phenylpiperazine referred to as "Compound (55)";

(56) 1-(5-isoquinolinesulfonyl)-4-benzylpiperazine referred to as "Compound (56)";

(57) 1-(5-isoquinolinesulfonyl)-4-phenethylpiperazine referred to as "Compound (57)";

(58) 1-(5-isoquinolinesulfonyl)-4-benzoylpiperazine referred to as "Compound (58)";

(59) 1-(5-isoquinolinesulfonyl)-4-cinnamylpiperazine referred to as "Compound (59)";

(60) 1-(5-isoquinolinesulfonyl)-4-cinnamoylpiperazine referred to as "Compound (60)";

(61) 1-(5-isoquinolinesulfonyl)-4-furoylpiperazine referred to as "Compound (61)";

(62) 1-(5-isoquinolinesulfonyl)-4-(2-methoxy-2-phenylethyl)piperazine referred to as "Compound (62)";

(63) 1-(5-isoquinolinesulfonyl)-4-(2-ethoxy-2-phenylethyl)piperazine referred to as "Compound (63)";

(64) 1-(5-isoquinolinesulfonyl)-4-(2-isobutoxy-2-phenylethyl)piperazine referred to as "Compound (64)";

(65) N-[2-(N-methyl-N-benzylamino)ethyl]-5-isoquinolinesulfonamide referred to as "Compound (65)";

(66) N-[2-(N-ethyl-N-benzylamino)ethyl]-5-isoquinolinesulfonamide referred to as "Compound (66)";

(67) N-[2-(N-isopropyl-N-benzylamino)ethyl]-5-isoquinolinesulfonamide referred to as "Compound (67)";

(68) 1-(5-isoquinolinesulfonyl)-3,3-dimethylpiperazine referred to as "Compound (68)";

and the pharmaceutically acceptable acid addition salts thereof.

The acid addition salts of the isoquinolinesulfonyl derivatives of Formula (I) according to this invention are pharmaceutically acceptable non-toxic salts and can be prepared by conventional methods.

Suitable examples of such pharmaceutically acceptable acid addition salts include the salts of inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, and sulfuric acid; and the salts of organic acids such as acetic acid, citric acid, tartaric acid, lactic acid, succinic acid, fumaric acid, maleic acid, methanesulfonic acid and p-toluenesulfonic acid.

The isoquinolinesulfonyl derivatives of Formula (I) of this invention can be prepared by reacting a 5-isoquinolinesulfonyl chloride of Formula (II) with a compound of Formula (III) in accordance with the following equation: ##STR29## wherein l, m, n, R₁, R₂ and R₃ are the same as defined above.

Exemplary compounds of Formula (III) include 1,2-diaminoethane, 1,3-diaminopropane, 1,4-diaminobutane, 1,5-diaminopentane, 1,6-diaminohexane, 1,8-diaminooctane, 1,10-diaminodecane, methylamine, ethylamine, n-propylamine, isopropylamine, n-butylamine, isobutylamine, n-hexylamine, dimethylamine, diethylamine, di-n-2-(N-methyl-N-benzylamino)ethylamine, 2-(N-ethyl-N-benzylamino)ethylamine, 2-(N-isopropyl-N-benzylamino)ethylamine, butylamine, di-n-hexylamine, 3-(N,N-dimethylamino)propylamine, 3-(N,N-diethylamino)propylamine, 3-(di-n-propylamino)propylamine, 3-diisopropylamino)propylamine, 3-(di-n-butylamino)propylamine, 3-(diisobutylamino)propylamine, 3-(N-methyl-N-cyclohexylamino)propylamine, 3-(N-methyl-N-phenylamino)propylamine, 3-(N-methyl-N-benzylamino)propylamine, 3-piperidinopropylamine, 3-pyrrolidinopropylamine, 3-morpholinopropylamine, piperidine, piperazine, morpholine, pyrrolidine, 2-methylpiperazine, 1-methylpiperazine, 2-ethylpiperazine, 1-ethylpiperazine, 2-n-propylpiperazine, 1-n-propylpiperazine, 2-isopropylpiperazine, 1-isopropylpiperazine, 2-n-butylpiperazine, 1-n-butylpiperazine, 2-isobutylpiperazine, 1-isobutylpiperazine, 2-n-hexylpiperazine, 1-n-hexylpiperazine, 2,2-dimethylpiperazine, 2,3-dimethylpiperazine, 2,5-dimethylpiperazine, 2,6-dimethylpiperazine, 2,5-diethylpiperazine, 2-isobutyl-5-methylpiperazine, 2-benzyl-5-methylpiperazine, 2-phenylpiperazine, 1-phenylpiperazine, 2-benzylpiperazine, 1-benzylpiperazine, 1-phenethylpiperazine, 1-benzoylpiperazine, 1-cinnamylpiperazine, 1-cinnamoylpiperazine, 1-furoylpiperazine, 1-(2-methoxy-2-phenylethyl)piperazine, 1-(2-ethoxy-2-phenylethyl)piperazine and 1-(2-isobutoxy-2-phenylethyl)piperazine.

The reaction between the compound of Formula (II) and the compound of Formula (III) can be carried out in the presence of absence of an acid acceptor. Exemplary acid acceptor which can be employed include alkali metal compounds such as a hydroxide, bicarbonate, carbonate, hydride or an alkoxide, e.g. sodium bicarbonate, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride and sodium alkoxides such as sodium methoxide, sodium ethoxide and sodium tert-butoxide; and organic tertiary amines such as trimethylamine, triethylamine, 1,4-diazabicyclo[2,2,2]octane and pyridine.

In general, this reaction is carried out in the presence of a reaction medium. Exemplary reaction media which can be employed include halogenated hydrocarbons such as chloroform and dichloromethane; alcohols such as methanol, ethanol and butanol; ethers such as tetrahydrofuran and dioxane; N,N-dimethylformamide, dimethyl sulfoxide, acetonitrile and water. The reaction media may be used singly or in combination with one another.

The amount of the compound of Formula (III) which can be employed is at least 1 mol and typically ranges from 1 to about 20 mols, preferably from 1 to 10 mols per mol of the compound of Formula (II). A more preferred amount of the compound of Formula (III) ranges from 1 to 5 mols per mol of the compound of Formula (II) when the acid acceptor is present, and from 2 to 10 mols per mol of the compound of Formula (II) when the acid acceptor is absent. This amount, however, does not apply to amines having a low boiling point such as methylamine and ethylamine.

The amount of the acid acceptor employed is preferably about 0.5 to about 10 equivalents and more preferably about 1 to about 6 equivalents for each mol of the compound of Formula (III).

The reaction between the compound of Formula (II) and the compound of Formula (III) can be carried out typically at a temperature of from about -30° C. to about 150° C. and preferably from about 0° C. to about 30° C.

While this reaction can be carried out at a pressure above atmospheric, it is generally advisable to utilize atmospheric pressure.

The reaction time which can be employed is typically about 0.5 to about 48 hours and preferably about 0.5 to 20 hours at atmospheric pressure.

Also, when R₂ in Formula (I) is a hydrogen atom, the 5-isoquinolinesulfonyl derivatives of this invention represented by Formula (VI) can be prepared by the following equations: ##STR30##

Further, when l in Formula (I) is zero, the ##STR31## group in Formula (I) is a ##STR32## group and R₆ is a hydrogen atom, the 5-isoquinolinesulfonyl derivatives of this invention represented by Formula (IX) can be prepared in accordance with the following equations: ##STR33##

In these Formulae, l, m, n, R₁, R₃, R₄ and R₅ are the same as defined above and X is a protective group. Exemplary protective groups represented by X which can be employed in this invention include acyl groups such as formyl, acetyl and benzoyl; arylmethyloxycarbonyl groups such as benzyloxycarbonyl; alkyloxycarbonyl groups such as tert-butoxycarbonyl; and benzyl group.

Exemplary compounds of Formulae (IV) and (VII) include N¹ -acetyl-1,2-diaminoethane, N¹ -acetyl-1,3-diaminopropane, N¹ -acetyl-1,4-diaminobutane, N¹ -acetyl-1,5-diaminopentane, N¹ -acetyl-1,6-diaminohexane, N¹ -acetyl-1,8-diaminooctane, N¹ -acetyl-1,10-diaminodecane, 2-benzyloxycarbonylamino-1-methylethylamine, 1-(benzyloxycarbonylaminomethyl)propylamine, 1-(benzyloxycarbonylaminomethyl)pentylamine, 2-(benzyloxycarbonylamino)propylamine, 2-(benzyloxycarbonylamino)-3-methylbutylamine, 2-acetamidopropylamine, 2acetamido-3-methylbutylamine, 2-acetamido-2-phenylethylamine, 2-(N-benzyl-N-methylamino)ethylamine, 2-(N-benzyl-N-ethylamino)ethylamine, 2-(N-benzyl-N-isopropylamino)ethylamine, 2-(benzyloxycarbonylamino)-1-phenylethylamine, 2-(benzyloxycarbonylamino)-2-phenylethylamine, 1-formyl-3-methylpiperazine, 1-acetyl-3-methylpiperazine, 1-benzyloxycarbonyl-3-methylpiperazine, 1-t-butyloxycarbonyl-3-methylpiperazine, 1-benzyl-3-methylpiperazine, 1-benzyloxycarbonyl-3-ethylpiperazine and 1-benzyloxycarbonyl-3-phenylpiperazine.

The reaction between the compound of Formula (II) and the compound of Formula (IV) and the reaction between the compound of Formula (II) and the compound of Formula (VII) can be carried out under the same reaction conditions as in the reaction between the compound of Formula (II) and the compound of Formula (III) to give the compound of Formula (V) and the compound of Formula (VIII), respectively. The method of obtaining the desired compound of Formula (VI) and the desired compound of Formula (IX) from the compound of Formula (V) and the compound of Formula (VIII), respectively, may vary depending upon the protective group of X selected, generally known methods can be employed in this invention. For example, when the protective group of X is an acyl group such as formyl or acetyl, the desired compounds can be obtained by hydrolysis with an acid or an alkali. When the protective group of X is a benzyl group, the desired compounds can be obtained by hydrogenation. When the protective group of X is an arylmethyloxycarbonyl group such as benzyloxycarbonyl, the desired compounds can be obtained by hydrogenation or hydrolysis with an acid. When the protective group of X is an alkyloxycarbonyl group such as tert-butoxycarbonyl, the desired products can be obtained by hydrolysis with an acid.

Furthermore, when l in Formula (I) is zero, the ##STR34## group in Formula (I) is a ##STR35## group and R₆ is not a hydrogen atom, the 5-isoquinolinesulfonyl derivatives of this invention represented by Formula (XII) can be prepared in accordance with the following equations: ##STR36##

In these Formulae, R₄, R₅ and R₆ are the same as defined above and W is an elimination group. Exemplary elimination groups include halogen atoms such as chlorine, bromine and iodine; substituted sulfonyloxy groups such as p-toluenesulfonyloxy and methanesulfonyloxy; and sulfuric acid residue. Exemplary compounds of the formula, R₆ -W which can be employed include dimethyl sulfate, methyl iodide, diethyl sulfate, ethyl bromide, n-propyl iodide, n-propyl bromide, isopropyl bromide, n-butyl bromide, isobutyl bromide, n-hexyl bromide, n-hexyl-p-toluenesulfonate, benzyl chloride, benzyl bromide, phenethyl bromide, benzoyl chloride, cinnamyl chloride, cinnamoyl chloride, furoyl chloride, 2-methoxy-2-phenylethyl bromide, 2-ethoxy-2-phenylethyl bromide and 2-isobutoxy-2-phenylethyl bromide.

In general, the reaction between the compound of Formula (XI) and the compound of R₆ -W can be carried out in the presence of an acid acceptor. Exemplary acid acceptors which can be employed include the same ones as employed in the reaction between the compound of Formula (II) and the compound of Formula (III).

This reaction is, in general, carried out in the presence of a reaction medium. Exemplary reaction media which can be employed include the same one as employed in the reaction between the compound of Formula (II) and the compounds of Formula (III).

The amount of the compound of R₆ -W which can be employed is at least 1 mol and typically ranges from 1 mol to about 20 mols, preferably from 1.2 mol to 10 mols per mol of the compound of Formula (XI).

The amount of the acid acceptor employed is preferably about 1 to about 10 equivalents and more preferably 1 to 4 equivalents for each mol of the compound of Formula (III).

The reaction between the compound of Formula (XI) and the compound of R₆ -W can be carried out typically at a temperature of from about -30° C. to about 200° C. and preferably from about 0° C. to about 100° C.

While this reaction may be carried out at a pressure above atmospheric or under reduced pressure, it is advisable to employ atmospheric pressure for practical purposes.

The method of separating and purifying the isoquinolinesulfonyl derivative of Formula (I) from the reaction solution comprises extracting the compound of Formula (I) with diluted hydrochloric acid, rendering the aqueous hydrochloric acid layer extracted basic, extracting the extract with a solvent such as chloroform capable of easily dissolving the extract, condensing the extract and subjecting the condensed residues to a silica gel column or an aluminum column chromatography for purification.

It has now been found that the isoquinolinesulfonyl derivatives of Formula (I) and the pharmaceutically acceptable salts have pharmacologically and biochemically interesting properties such as a relaxatory action for vascular smooth muscle and an action for increasing blood flow and are useful as a vasodilator, a hypotensor, an ameliorant of cerebral circulation, a medicine for angina pectoris and a preventive and a medicine for cardiovascular thrombosis.

The effect of the isoquinolinesulfonyl derivatives and the pharmaceutically acceptable acid addition salts of this invention on smooth muscle can be proved by suspending a mesenteric artery taken out from a rabbit in helical form, contracting the mesenteric artery with potassium chloride and adding the isoquinolinesulfonyl derivatives or their pharmaceutically acceptable acid addition salts of this invention to the contracted mesenteric artery, resulting in the relaxation of the mesenteric artery. When, for example, 1-(5-isoquinolinesulfonyl)-4-methylpiperazine, i.e., Compound (36) was added and a complete relaxation was designated 100%, the concentration which could bring about a relaxation of 50%, i.e., ED₅₀ was 7.7 μM, and with 1-(5-isoquinolinesulfonyl)piperazine, i.e., Compound (35) and N-(4-aminobutyl)-5-isoquinoline sulfonamide, i.e., Compound (3), ED₅₀ were 0.6 μM and 11 μM, respectively.

The effect of the isoquinolinesulfonyl derivatives and the pharmaceutically acceptable acid addition salts of this invention on the vasodilatation of the femoral and vertebral arteries can be measured by anesthetizing a dog of mixed breed weighting 8 to 15 Kg by an intravenous administration of 35 mg/Kg of pentbarbital, providing an acute type probe (a product of Nippon Koden K.K., Japan) with the femoral and vertebral arteries, administering the isoquinolinesulfonyl derivatives and the pharmaceutically acceptable acid addition salts to the femoral vein through a polyethylene tube inserted into the femoral vein side chain and measuring the blood flow volume with an electromagnetic flowmeter (a product of Nippon Koden K.K., Japan, "MF-27"). Among the isoquinolinesulfonyl compounds of Formula (I) of this invention, those with l=0 and the ##STR37## group show a high action for increasing blood flow and simultaneously a selectivity to vertebral arteries. For example, when 1 mg/Kg of 1-(5-isoquinolinesulfonyl)piperazine, i.e., Compound (35) was intravenously administered, the increased blood flow volumes in the vertebral artery and in the femoral artery were 98% and 65%, respectively. Also the isoquinolinesulfonyl compounds of Formula (I) of this invention with l=1 and one of the R₂ and R₃ groups=a hydrogen atom show a continuing blood flow increase. With 1 mg/Kg of N-(2-aminoethyl)-5-isoquinolinesulfonamide, i.e., Compound (1), an increase in the blood flow volume in the vertebral artery was continued for at least 30 minutes.

Furthermore, when the isoquinolinesulfonyl derivatives and the pharmaceutically acceptable acid addition salts of this invention are intravenously and arterially administered for the above described purposes, any remarkable toxicity cannot be observed. For example, the acute toxicity of 1-(5-isoquinolinesulfonyl)-4-methylpiperazine, i.e., Compound (36), i.e., LD₅₀ was 94 mg/Kg in giving male ddY-strain mice an intravenous administration.

The following examples illustrate the present invention in more detail, but they are given for illustrative purposes only and are not to be construed as limiting the invention.

The following examples illustrate the present invention in more detail, but they are given for illustrative purposes only and are not to be construed as limiting the invention.

EXAMPLE 1

In 200 ml of chloroform was dissolved 8.8 g of 1,4-diaminobutane, and to the solution was added dropwise 100 ml of a chloroform solution containing 4.55 g of 5-isoquinolinesulfonyl chloride under cooling with ice. After the dropwise addition of the chloroform solution, the mixed solution was stirred at a temperature of 20° C. to 25° C. for two hours, and then the reaction solution was extracted with a 10% aqueous hydrochloric acid solution. The pH of the aqueous layer was adjusted to 10 with a 10% aqueous sodium hydroxide solution, and the aqueous layer was extracted with chloroform. The chloroform layer extracted was washed with water and dried with anhydrous potassium carbonate. Then the chloroform was distilled from the chloroform layer, and the residue obtained was subjected to a column chromatography [silica gel: 200 g; developing solvent: 2% methanol/chloroform (volume ratio)] to give 3.46 g of N-(4-aminobutyl)-5-isoquinolinesulfonamide, i.e., Compound (3) as an oily substance in a yield of 62%.

Mass spectrum (m/e): 279(M⁺) and 221.

NMR spectrum (CDCl₃): 1.5˜2.0(4H, 2×CH₂), 2.5˜3.2(4H, 2×NCH₂), 2.4(2H, NH₂), 7.5˜7.7(1H), 7.9˜8.7(4H) and 9.3(1H).

IR absorption spectrum (ν_(max) ^(cap), cm⁻¹): 1330 and 1160.

The same procedures as described above were repeated using the compounds of Formula (III) as set forth in Table 1-1 under the reaction conditions as set forth in Table 1-1, and N-(ω-aminoalkyl)-5-isoquinoline sulfonamides as set forth in Table 1-2 were obtained. The results and the analytical values of these compounds are shown in Table 1-2.

                                      TABLE 1-1                                    __________________________________________________________________________      Run                                                                               ##STR38##  Compound of Formula (III)                                                                    TemperatureReaction                                                                   TimeReaction                               No.                                                                               (g)        (g)           (°C.)                                                                          (hour)                                      __________________________________________________________________________     1  4.55       H.sub.2 N(CH.sub.2).sub.2 NH.sub.2                                                       12.0                                                                               15˜20                                                                           2                                           2  3.41       H.sub.2 N(CH.sub.2).sub.3 NH.sub.2                                                       11.1                                                                               "      2                                           3  4.55       H.sub.2 N(CH.sub.2).sub.6 NH.sub.2                                                       11.6                                                                               "      5                                           4  2.28       H.sub.2 N(CH.sub.2).sub.10 NH.sub.2                                                      8.62                                                                               "      10                                          __________________________________________________________________________

                                      TABLE 1-2                                    __________________________________________________________________________               ##STR39##   Mass                                                                                AbsorptionIR                                        Run                                                                               Compound   Yield  Spectrum                                                                            Spectrum                                                                              NMR Spectrum                                  No.                                                                               No.   n    [g (%)]                                                                               (m/e)                                                                               (.sup.ν SO.sub.2, cm.sup.-1)                                                       (CDCl.sub.3)                                  __________________________________________________________________________     1  (1)   2    3.3                                                                               (66)                                                                               222, 221                                                                            3400, 1610                                                                            1.5(2H, N .sub.--H.sub.2), 2.9(4H, 2                                           × C .sub.--H.sub.2)                                          193, 129                                                                            1330, 1165                                                                            7.58˜7.9(1H), 8.0˜8.7(4H)                              128  1145, 1190                                                                            9.33(1H)                                                                1030, 830                                            2  (2)   3    2.9                                                                               (73)                                                                               265, 236                                                                            3400, 1610                                                                            1.4˜1.9(2H, C .sub.--H.sub.2)                                221, 143                                                                            1350, 1330                                                                            2.5˜3.2(4H, 2 × NC .sub.--H.s                                      ub.2)                                                              128  1160, 1145                                                                            3.21(2H, N .sub.--H.sub.2), 7.62(1H)                                    1090, 830                                                                             8.0˜8.8(4H), 9.33(1H)                   3  (4)   6    4.6                                                                               (75)                                                                               307, 277                                                                            1590, 1320                                                                            1.0˜2.0(8H), 2.9˜3.2(4H)                               263, 243                                                                            1140, 1120                                                                            7.65(1H), 8.0˜8.8(4H)                                        221, 192                                                                            1060, 810                                                                             9.33(1H)                                                           128                                                       4  (5)   10   2.2                                                                               (61)                                                                               363, 320                                                                            3400, 1590                                                                            1.3(16H, 8 × C .sub.--H.sub.2)                               292, 221                                                                            1350, 1330                                                                            2.5˜3.2(4H, 2 × NC .sub.--H.s                                      ub.2)                                                              192, 128                                                                            1160, 1140                                                                            3.3(2H, N .sub.--H.sub.2), 7.0(1H, N                                           .sub.--H)                                                                      7.6(1H), 8.1˜8.8(4H)                                                     9.3(1H)                                       __________________________________________________________________________

EXAMPLE 2

In 50 ml of dichloromethane was dissolved 1.73 g of 5-isoquinolinesulfonyl chloride, and to the solution were added 1.54 g of triethylamine and 8.0 g of monomethylamine hydrochloride. The mixture was stirred at a temperature of 10° C. to 15° C. for 18 hours. The reaction solution obtained was washed with water, dried with magnesium sulfate, and then the dichloromethane was distilled therefrom under reduced pressure. The residue obtained was subjected to a silica gel column chromatography (silica: 50 g; solvent: chloroform) to give 1.30 g of N-methyl-5-isoquinolinesulfonamide, i.e., Compound (25) in a yield of 77%.

Mass spectrum (m/e): 208, 148 and 128.

NMR spectrum (CDCl₃): 2.63(3H, singlet, NCH₃), 3.23(1H, NH), 7.4˜7.7(1H), 8.1˜8.7(4H) and 9.3(1H).

IR absorption spectrum (ν_(max) ^(cap), cm⁻¹): 3050, 2920, 1610, 1580, 1440, 1365, 1320, 1210, 1150, 1130 and 1080.

The same procedures as described above were repeated using the compounds of Formula (III) as set forth in Table 2-1 under the reaction conditions as set forth in Table 2-1, and there were obtained N-ethyl-5-isoquinolinesulfonamide, i.e., Compound (26); N,N-dimethyl-5-isoquinolinesulfonamide, i.e., Compound (29); and N,N-diethyl-5-isoquinolinesulfonamide, i.e., Compound (30). The results and the analytical values of these compounds are shown in Table 2-2.

                                      TABLE 2-1                                    __________________________________________________________________________      Run                                                                               ##STR40##  Compound of Formula (III)                                                                    N(C.sub.2 H.sub.5).sub.3                                                            TemperatureReaction                                                                   TimeReaction                          No.                                                                               (g)        (g)           (g)  (°C.)                                                                          (hour)                                 __________________________________________________________________________     1  2.28       H.sub.2 N(C.sub.2 H.sub.5).HCl                                                           8.2 10   15˜25                                                                           24                                     2  "          HN(CH.sub.3).sub.2.HCl                                                                   8.2 10   "      20                                     3  1.50       HN(C.sub.2 H.sub.5).sub.2.HCl                                                            7.2 6.6  "      "                                      __________________________________________________________________________

                                      TABLE 2-2                                    __________________________________________________________________________               ##STR41##    Mass                                                                                AbsorptionIR                                       Run                                                                               Compound     Yield Spectrum                                                                            Spectrum                                                                              NMR Spectrum                                 No.                                                                               No.   Y      [g (%)]                                                                              (m/e)                                                                               (ν.sup.cap .sub.max, cm.sup.-1)                                                    (CDCl.sub.3)                                 __________________________________________________________________________     1  (26)  NH(C.sub.2 H.sub.5)                                                                   1.93                                                                              (81)                                                                              236, 164                                                                            3050, 2920                                                                            1.15(3H, triplet)                                                  128  1600, 1560                                                                            2.73(2H, quartet)                                                       1440, 1360                                                                            3.33(1H, singlet, N .sub.--H)                                           1300, 1200                                                                            7.4˜7.7(1H)                                                       1150, 1070                                                                            8.1˜8.7(4H), 9.32(1H)                  2  (29)  N(CH.sub.3).sub.2                                                                     1.77                                                                              (75)                                                                              236, 191                                                                            1600, 1470                                                                            2.85(6H, 2 × C .sub.--H.sub.3)                               143, 128                                                                            1440, 1320                                                                            7.5˜7.9(1H)                                                       1145, 1125                                                                            8.2˜8.5(4H), 9.3(1H)                                              1035, 975                                                                      940                                                 3  (30)  N(C.sub.2 H.sub.5).sub.2                                                              1.34                                                                              (77)                                                                              264, 235                                                                            1600, 1460                                                                            1.2˜1.4(6H, 2 × C .sub.--H.s                                       ub.3)                                                              191, 143                                                                            1360, 1150                                                                            2.2˜3.3(4H, 2 × N .sub.--CH.                                       sub.2)                                                                  1120, 1050                                                                            7.5˜8.6(5H), 9.3(1H)                   __________________________________________________________________________

EXAMPLE 3

In 100 ml of methylene chloride were added 6.0 g of piperazine and 1.2 g of anhydrous potassium carbonate, and to the mixture was added dropwise 30 ml of a methylene chloride solution containing 2.0 g of 5-isoquinolinesulfonyl chloride under cooling with ice. After the dropwise addition of the methylene chloride solution, the mixed solution was stirred at a temperature of 15° C. to 25° C. for 15 hours, and then the reaction solution was washed with water, dried with anhydrous magnesium sulfate, and the methylene chloride was distilled therefrom. The residue thus obtained was subjected to a silica gel column chromatography (silica gel: 70 g; solvent: chloroform) to give 2.14 g of 1-(5-isoquinolinesulfonyl)piperazine, i.e., Compound (35) in a yield of 89%.

Mass spectrum (m/e): 277, 234, 212, 191 and 128.

NMR spectrum (CDCl₃): 1.65(1H, NH), 2.8˜3.3(8H, 4×NCH₂), 7.5˜7.9(1H), 8.2˜8.7(4H) and 9.35(1H).

IR absorption spectrum (ν_(max) ^(KBr), cm⁻¹): 3350, 1600, 1560, 1540, 1370 and 1160.

EXAMPLE 4

In 100 ml of dichloromethane was dissolved 2.28 g of 5-isoquinolinesulfonyl chloride, and to the solution were added 1.38 g of anhydrous potassium carbonate and 1.46 g of n-butylamine, and the mixture thus obtained was stirred at a temperature of 20° C. to 25° C. for 12 hours. The reaction solution was washed with water, dried with anhydrous magnesium sulfate, and the dichloromethane was distilled therefrom under reduced pressure. The residue thus obtained was subjected to a silica gel column chromatography (silica gel: 70 g; solvent: chloroform) to give 1.90 g of N-n-butyl-5-isoquinolinesulfonamide, i.e., Compound (27) in a yield of 72%.

Mass spectrum (m/e): 264, 211 and 191.

NMR spectrum (CDCl₃): 0.7˜1.6(7H, C₃ H₇), 2.67(2H, NCH₂), 3.46(1H, NH), 7.4˜7.8(1H), 8.1˜8.6(4H) and 9.3(1H).

IR absorption spectrum (ν_(max) ^(cap), cm⁻¹): 3070, 2920, 1610, 1580, 1450, 1360, 1300, 1150, 1080.

The same procedures as described above were repeated using the compounds of Formula (III) as set forth in Table 3-1 under the reactiton conditions as set forth in Table 3-1, and there were obtained N-isobutyl-5-isoquinolinesulfonamide, i.e., Compound (28); N,N-di-n-butyl-5-isoquinolinesulfonamide, i.e., Compound (31); 1-(5-isoquinolinesulfonyl)piperazine, i.e., Compound (32); 1-(5-isoquinolinesulfonyl)pyrrolidine, i.e., Compound (33); and 1-(5-isoquinolinesulfonyl)morpholine, i.e., Compound (34). The results and the analytical values of these compounds are shown in Table 3-2.

                                      TABLE 3-1                                    __________________________________________________________________________      Run                                                                               ##STR42##  Compound of Formula (III)                                                                    CarbonatePotassiumAnhydrous                                                          TemperatureReaction                                                                   TimeReaction                         No.                                                                               (g)        (g)           (g)   (°C.)                                                                          (hour)                                __________________________________________________________________________     1  3.0        H.sub.2 N(i-C.sub.4 H.sub.9)                                                            2.4  2.1   20˜25                                                                            5                                    2  2.5        HN(n-C.sub.4 H.sub.9).sub.2                                                             3.6  1.6   "      18                                    3  3.0                                                                                        ##STR43##                                                                              2.8  2.1   "      12                                    4  "                                                                                          ##STR44##                                                                              2.5  "     "      "                                     5  "                                                                                          ##STR45##                                                                              2.8  "     "      "                                     __________________________________________________________________________

                                      TABLE 3-2                                    __________________________________________________________________________               ##STR46##     Mass                                                                                AbsorptionIR                                      Run                                                                               Compound      Yield Spectrum                                                                            Spectrum                                                                              NMR Spectrum                                No.                                                                               No.   Y       [g (%)]                                                                              (m/e)                                                                               (ν.sup.cap .sub.max, cm.sup.-1)                                                    (CDCl.sub.3)                                __________________________________________________________________________     1  (28)  NH(i-C.sub.4 H.sub.9)                                                                  2.37                                                                              (68)                                                                              264, 211                                                                            3070, 2920                                                                            0.7˜1.1(6H, 2 × C .sub.--H.                                        sub.3)                                                             191  1610, 1580                                                                            1.0˜1.5(1H, C .sub.--H)                                           1440, 1365                                                                            2.55(2H, NC .sub.--H.sub.2)                                             1320, 1210                                                                            3.62(1H, N .sub.--H),                                                          7.5˜7.8(1H)                                                       1150, 1090                                                                            8.1˜8.6(4H), 9.3(1H)                  2  (31)  N(n-C.sub.4 H.sub.9).sub.2                                                             2.43                                                                              (69)                                                                              320, 234                                                                            1600, 1470                                                                            0.9˜1.9(14H, 2 × C                                                 .sub. --.sub.2 C .sub.--H.sub.2 C                                              .sub.--H.sub.3)                                                    191, 143                                                                            1360, 1150                                                                            2.9˜3.5(4H, 2 × NC                                                 .sub.--H.sub.2)                                                                7.5˜8.8(5H), 9.3(1H)                  3  (32)                                                                                  ##STR47##                                                                             2.6                                                                               (71)                                                                              276, 211 191, 127                                                                   1600, 1560 1470, 1370 1150                                                            1.4˜1.9(6H, 3 × C .sub.--H.                                        sub.2) 3.0˜3.3(4H, 2 × NC                                          .sub.--H.sub.2) 7.6˜7.9(1H),                                             8.2˜8.8(4H) 9.4(1H)                   4  (33)                                                                                  ##STR48##                                                                             2.94                                                                              (85)                                                                              262, 211 191, 127                                                                   1600, 1550 1470, 1350 1150                                                            1.3˜1.9(4H, 2 × C .sub.--H.                                        sub.2) 3.0˜3.5(4H, 2 × NC                                          .sub.--H.sub.2) 7.6˜7.9(1H)                                              8.2˜8.8(4H), 9.3(1H)                  5  (34)                                                                                  ##STR49##                                                                             2.9                                                                               (79)                                                                              278, 234 213, 191  127                                                              1590, 1560 1540, 1470 1370,                                                           3.0˜3.3(4H, 2 × NC                                                 .sub.--H.sub.2) 3.6˜3.8(4H, 2                                            × OC .sub.--H.sub.2) 7.5˜7.                                        9(1H) 8.0˜8.7(4H),                    __________________________________________________________________________                                        9.3(1H)                                

EXAMPLE 5

In 50 ml of a chloroform solution containing 1.4 g of 3-dimethylaminopropylamine and 1.4 g of triethylamine was added dropwise 30 ml of a chloroform solution containing 2.6 g of 5-isoquinolinesulfonyl chloride under cooling with ice. After the dropwise addition of the chloroform solution, the mixed solution was stirred at a temperature of 2° C. to 10° C. for four hours, and the reaction mixture solution was washed with water and dried with anhydrous magnesium sulfate. After the chloroform was distilled therefrom, the residue obtained was subjected to a silica gel column chromatography (silica gel: 70 g; solvent: chloroform) to give 2.38 g of N-(3-dimethylaminopropyl)-5-isoquinolinesulfonamide, i.e., Compound (17) in a yield of 71%.

Mass spectrum (m/e): 293, 249, 235, 221 and 207.

NMR spectrum (CDCl₃): 1.6(2H, CH₂), 2.0˜2.6(8H, 2×NCH₃ +NCH₂), 3.1(2H, NCH₂), 6.2(NH), 7.4˜7.7(1H), 8.0˜8.6(4H) and 9.3(1H).

IR absorption spectrum (ν_(max) ^(cap), cm⁻¹): 2950, 2860, 2840, 1460, 1320, 1150, 1130, 830 and 760.

The same procedures as described above were repeated using the compounds of Formula (III) as set forth in Table 4-1 under the reaction conditions as set forth in Table 4-1, and there were obtained N-(3-diethylaminopropyl)-5-isoquinolinesulfonamide, i.e., Compound (18); N-(3-di-n-butylaminopropyl)-5-isoquinolinesulfonamide, i.e., Compound (19); N-(3-piperidinopropyl)-5-isoquinolinesulfonamide, i.e., Compound (20); N-(3-morpholinopropyl)-5-isoquinolinesulfonamide, i.e., Compound (21); N-[3-(N-methyl-N-cyclohexylamino)propyl]-5-isoquinolinesulfonamide, i.e., Compound (22); N-[3-(N-methyl-N-phenylamine)propyl]-5-isoquinolinesulfonamide, i.e., Compound (23); and N-[3-(N-methyl-N-benzylamino)propyl]-5-isoquinolinesulfonamide, i.e., Compound (24). The results and the analytical values of these compounds are shown in Table 4-2.

                                      TABLE 4-1                                    __________________________________________________________________________      Run                                                                               ##STR50##                                                                                 ##STR51##          N(C.sub.2 H.sub.5).sub.3                                                            TemperatureReaction                                                                   TimeReaction                     No.                                                                               (g)        (g)                (g)  (°C.)                                                                          (hour)                            __________________________________________________________________________     1  1.0        H.sub.2 N(CH.sub.2).sub.3 N(C.sub.2 H.sub.5).sub.2                                             0.7                                                                                0.67                                                                               2˜5                                                                              5                                2  "          H.sub.2 N(CH.sub.2).sub.3 N(n-C.sub.4 H.sub.9).sub.2                                           1.0                                                                               "     5˜10                                                                           "                                 3  "                                                                                          ##STR52##      0.8                                                                               "    10˜20                                                                           12                                4  "                                                                                          ##STR53##      0.8                                                                               "    15˜25                                                                           18                                5  0.44                                                                                       ##STR54##      0.4                                                                               0.3  "      "                                 6  "                                                                                          ##STR55##      0.38                                                                              "    "      "                                 7  0.75                                                                                       ##STR56##      0.75                                                                              0.5  "      "                                 __________________________________________________________________________

                                      TABLE 4-2                                    __________________________________________________________________________               ##STR57##                                                             No.Run                                                                            No.Compound                                                                          ##STR58##   [g(%)]Yield                                                                          (m/e)SpectrumMass                                                                   (ν .sub.max, cm.sup.-1).sup.capSpectru                                     mApsorptionIR                                                                          (CDCl.sub.3)NMR                        __________________________________________________________________________                                            Spectrum                                1  (18)                                                                                  ##STR59##  0.75 (53)                                                                            321, 249 235, 221 207, 192                                                          2950, 2850 1460, 1320 1160,                                                           1.1(6H, 2 × C .sub.--H.sub.3)                                             1.5˜2.0(2H,                                                             C .sub.--H.sub.2) 2.0˜2.6(6H,                                             3 × NC  .sub.--H.sub.2)                                                 3.1(2H, NC .sub.--H.sub.2),                                                    6.8(1H, N .sub.--H) 7.6(1H,                                                    8.0˜8.5(4H) 9.3(1H)               2  (19)                                                                                  ##STR60##  0.93 (56)                                                                            377, 334 296, 248 234, 220 140                                                      2960, 2870 1460, 1325 1155,                                                           0.8˜2.0(16H, 2 × C                                                 .sub.--H.sub.3 + 5 × C                                                   .sub.--H.sub.2) 2.2˜2.8(6H,                                              3 × NC .sub.--H.sub.2)                                                   3.1(2H, NC .sub.--H.sub.2),                                                    5.4(1H, N .sub.--H) 7.7(1H,                                                    8.1˜8.7(4H), 9.3(1H)              3  (20)                                                                                  ##STR61##  0.72 (49)                                                                            332, 248 234, 220 206, 191                                                          3075, 2920 2850, 2800 1320,                                                           1.3˜2.0(8H, 4 × C                                                  .sub.--H.sub.2) 2.0˜2.6(6H,                                              3 × NC .sub.--H.sub.2)                                                   3.0(2H, NC .sub.-- H.sub.2),                                                   6.8(1H, N .sub.--H) 7.6(1H),                                                   8.1˜8.7(4H), 9.3(1H)              4  (21)                                                                                  ##STR62##  0.63 (43)                                                                            334, 278 276, 248 234, 221 192,                                                     2950, 2850 2820, 1320 1160, 1140 1120,                                         760    1.3˜1.9(2H,                                                              C .sub.--H.sub.2) 2.0˜2.7(6H,                                             3 × NC .sub.--H.sub.2)                                                  3.0(2H, NC .sub.--H.sub.2)                                                     3.4˜3.9(4H, 2 × OC                                                 .sub.--H.sub.2) 6.5˜7.1(1H,                                              N .sub.--H), 7.7(1H) 8.1˜8.8(                                            4H), 9.4(1H)                            5  (22)                                                                                  ##STR63##  0.43 (62)                                                                            361, 318 249, 221 192, 169 126                                                      2930, 2850 1330, 1160 1140,  790                                                      0.7˜1.8(12H, 6 × C                                                 .sub.--H.sub.2) 2.1(3H, NC                                                     .sub.--H.sub.3) 2.1˜2.8(3H,                                              NC .sub.-- H.sub.2 + NC .sub.--H)                                              2.7˜3.1(2H,                                                              NC .sub.--H.sub.2) 7.1˜7.5(1H                                            , N .sub.--H), 7.5(1H) 7.9˜8.                                            7(4H), 9.2(1H)                          6  (23)                                                                                  ##STR64##  0.27 (39)                                                                            355, 163 134, 128 120                                                               3050, 2900 2850, 1620 1500, 1330 1160,                                         1135  830,  750                                                                       1.5˜1.9(2H), 2.7(3H, NC                                                  .sub.--H.sub.3) 2.8˜3.4(4H,                                              2 × NC .sub.--H.sub.2)                                                   6.2(1H, N .sub.--H),                                                           6.5˜6.8(3H) 6.9˜7.3(2H)                                            , 7.6(1H) 8.0˜8.6(4H),                                                   9.25(1H)                                7  (24)                                                                                  ##STR65##  0.86 (71)                                                                            369, 354 278, 221 177, 134 128,                                                     3050, 2950 2850, 2800 1620, 1450 1330,                                         1210 1155, 1135                                                                       1.3˜1.9(2H,                                                              C .sub.--H.sub.2), 1.95(3H, NC                                                 .sub.--H.sub.3) 2.3˜2.7(2H,                                              NC .sub. --H.sub.2) 3.0˜3.3(2                                            H, NC .sub.--H.sub.2) 3.3(2H,                                                  C.sub.6 H.sub.5 C .sub.--H.sub.2)                                              7.0˜7.1(1H, N .sub.--H)                                                  7.2(5H, C.sub.6  .sub.--H.sub.5),                                              7.6(1H) 8.0˜8.5(4H),              __________________________________________________________________________                                            9.3(1H)                            

EXAMPLE 6

In 100 ml of chloroform was dissolved 5.0 g of 1-methylpiperazine, and to the solution was added 6.9 g of anhydrous potassium carbonate. To the mixture was added dropwise 200 ml of a chloroform solution containing 1.4 g of 5-isoquinolinesulfonyl chloride under cooling with ice. After the dropwise addition of the chloroform solution, the mixed solution thus obtained was stirred for one hour under cooling with ice, and then the reaction solution was washed with 50 ml of a 5N aqueous sodium hydroxide solution and extracted twice with 50 ml of a 5N aqueous hydrochloric acid solution. The aqueous hydrochloric acid layer was rendered alkaline, extracted three times with 100 ml of chloroform, and the chloroform layer extracted was washed with water and dried with anhydrous magnesium sulfate. After the chloroform was distilled therefrom under reduced pressure, 50 ml of a 5N aqueous hydrochloric acid solution was added to the residue and the mixture was condensed to dryness under reduced pressure. The crystalline residue thus obtained was recrystallized from ethanol to give 14.9 g of 1-(5-isoquinolinesulfonyl)-4-methylpiperazine [i.e., Compound (36)] dihydrochloride in a yield of 82%.

Melting point: 215° C.

Mass spectrum (m/e): 291(M+1), 128 and 99.

NMR spectrum (CDCl₃, δ): 2.9(3H, s, CH₃), 3.0˜4.0(8H, m, 4×CH₂), 7.8˜8.1(1H), 8.5˜8.8(4H) and 9.6(1H, s)

IR absorption spectrum (ν_(max) ^(KBr), cm⁻¹): 3400, 1610, 1378, 1350, 1160 and 1140.

EXAMPLE 7

In 100 ml of ethanol were added 2.77 g of 1-(5-isoquinolinesulfonyl)piperazine, i.e., Compound (35), 1.66 g of anhydrous potassium carbonate and 5.45 g of ethyl bromide, and the reaction was carried out at an external temperature of 70° C. for 24 hours. After the reaction solution was filtered, the filtrate was condensed and the residue was dissolved in 50 ml of chloroform, and the solution was extracted twice with a 2N aqueous hydrochloric acid solution. The aqueous hydrochloric acid layer was rendered alkaline, extracted twice with 50 ml of chloroform, and the chloroform layer extracted was washed with water and dried with anhydrous magnesium sulfate. After the chloroform was distilled therefrom, the residue obtained was subjected to a silica gel column chromatography (silica gel: 100 g; solvent: 2% methanol-chloroform) to give 2.26 g of 1-(5-isoquinolinesulfonyl)-4-ethylpiperazine, i.e., Compound (42) in a yield of 74%.

Melting point (the dihydrochloride recrystallized from ethanol): 221° C.

Mass spectrum (m/e): 305(M⁺), 290(M-15), 277, 128 and 113.

NMR spectrum (CDCl₃, δ): 0.9(3H, t, CH₃), 2.2˜2.8(6H, m, 3×CH₂), 2.9˜3.4(4H, m, 2×CH₂), 7.5˜8.9(5H, m) and 9.3(1H, s).

IR absorption spectrum (ν_(max) ^(cap), cm⁻¹): 1610, 1350, 1340 and 1140.

EXAMPLE 8

The same procedures as in Example 7 were repeated except that 3.7 g of propyl bromide was employed instead of the 5.45 g of ethyl bromide. As a result there was obtained 1.53 g of 1-(5-isoquinolinesulfonyl)-4-propylpiperazine, i.e., Compound (44) in a yield of 48%.

Melting point (the dihydrochloride recrystallized from ethanol): 214° C.

Mass spectrum (m/e): 319(M⁺), 290(M-29), 127 and 88.

NMR spectrum (CDCl₃, δ): 0.8(3H, t, CH₃), 1.0˜1.7(2H, m, 1×CH₂), 2.0˜2.7(6H, m, 3×NCH₂), 3.0˜3.3(4H, m, 2×NCH₂), 7.5˜8.7(5H, m) and 9.2(1H, s).

IR absorption spectrum (ν_(max) ^(cap), cm⁻¹): 1607, 1350, 1260, 1165 and 1140.

EXAMPLE 9

In 30 ml of chloroform were added 1.42 g of 1-isobutylpiperazine and 2.76 g of potassium carbonate, and to the mixture was added dropwise 50 ml of a chloroform solution containing 2.28 g of 5-isoquinolinesulfonyl chloride under cooling with ice. After the dropwise addition of the chloroform solution, the mixed solution thus obtained was stirred at a temperature of 15° C. to 25° C. for two hours, and then the reaction solution was washed with 20 ml of a 1N aqueous sodium hydroxide solution and extracted twice with a 5N aqueous hydrochloric acid solution. The aqueous hydrochloric acid layer was rendered alkaline extracted three time with 30 ml of chloroform, and the chloroform layer extracted was washed with water and dried with anhydrous magnesium sulfate. After the chloroform was distilled therefrom under reduced pressure, the residue obtained was subjected to a silica gel column chromatography (silica gel; 100 g; solvent: 2% methanol-chloroform) to give 2.60 g of 1-(5-isoquinolinesulfonyl)-4-isobutylpiperazine, i.e., Compound (47) in a yield of 78%.

Melting point (the dihydrochloride recrystallized from ethanol): 234° C.

Mass spectrum (m/e): 333(M⁺), 290(M-C₃ H₇), 141 and 128.

NMR spectrum (CDCl₃, δ): 0.8(6H, d, 2×CH₃), 1.2˜2.0(1H, m, CH), 2.0˜3.3(10H, 5×NCH₂), 7.6˜8.8(5H) and 9.3(1H, s).

IR absorption spectrum (ν_(max),^(cap) cm⁻¹): 3430, 1620, 1350, 1340, 1170 and 1145.

The same procedures as described above were repeated using the compounds of Formula (III) as set forth in Table 5-1 under the reaction conditions as set forth in Table 5-1, and there were obtained 1-(5-isoquinolinesulfonyl)-4-n-hexylpiperazine, i.e., Compound (51); 1-(5-isoquinolinesulfonyl)-phenylpiperazine, i.e., Compound (55); 1-(5-isoquinolinesulfonyl)-4-phenethylpiperazine, i.e., Compound (57); 1-(5-isoquinolinesulfonyl)-4-cinnamylpiperazine, i.e., Compound (59); and 1-(5-isoquinolinesulfonyl)-4-(2-ethoxy-4-phenylethyl)piperazine, i.e., Compound (63). The results and the analystical values of these compounds are shown in Table 5-2.

                                      TABLE 5-1                                    __________________________________________________________________________      No.Run                                                                            ##STR66##                                                                                 ##STR67##               (g)K.sub.2 CO.sub.3                                                                (°C.)TemperatureReaction                                                       (hour)TimeReaction           __________________________________________________________________________     1  2.28                                                                                       ##STR68##           1.70                                                                              2.76                                                                               15˜25                                                                           2                             2  "                                                                                          ##STR69##           1.62                                                                              "   "      "                             3  "                                                                                          ##STR70##           1.9                                                                               "   "      "                             4  "                                                                                          ##STR71##           2.1                                                                               "   "      "                             5  "                                                                                          ##STR72##           2.34                                                                              "   "      "                             __________________________________________________________________________

                                      TABLE 5-2                                    __________________________________________________________________________               ##STR73##    Mass    AbsorptionIR                                    Run                                                                               Compound     Yield Spectrum                                                                               Spectrum                                                                              NMR Spectrum                              No.                                                                               No.   R.sub.6                                                                               [g(%)]                                                                               (m/e)   (ν.sup.cap .sub.max, cm.sup.-1)                                                    (CDCl.sub.3)                              __________________________________________________________________________     1  (51)  n-C.sub.6 H.sub.13                                                                    2.64 (73)                                                                            361, 290                                                                               1620, 1460                                                                            0.6˜1.8(11H, 4 × C                                                 .sub.--H.sub.2 + C .sub.--H.sub.3)                              169, 98 1350, 1335                                                                            3.2˜3.7(6H, 3 × NC                                                 .sub.--H.sub.2)                                                         1170, 1140                                                                            3.1˜3.5(4H, 2 × NC                                                 .sub.--H.sub.2)                                                                7.4˜8.8(5H), 9.3(1H)                2  (55)                                                                                  ##STR74##                                                                            2.44 (69)                                                                            353, 278 161                                                                           3400, 1605  1360, 1170 1150                                                           3.8(8H, 4 × NC .sub.--H.sub.2)                                           .6(5H, C.sub.6  .sub.--H.sub.5)                                                7.6˜9.0(5H), 9.2(1H)                3  (57)                                                                                  ##STR75##                                                                            2.44 (64)                                                                            290 (MCH.sub.2 C.sub.6 H.sub.5)                                                        3400, 1350 1330, 1155  950                                                            2.5˜4.0(12H, 6 × C                                                 .sub.--H.sub.2) 7.3(5H),                                                       7.9˜9.0(5H) 9.8(1H) (d.sup.6                                             -dimethyl sulfoxide)                      4  (59)                                                                                  ##STR76##                                                                            3.58 (91)                                                                            394, 303 202, 117                                                                      3400, 1350 1165, 1140  935                                                            4.0(8H, 4 × NC .sub.--H.sub.2)                                           .9(2H, NC .sub.--H.sub.2 CH)                                                   6.0˜6.5(1H),                                                             6.9(1H) 7.3˜7.5(5H),                                                     8.0˜9.2(5H) 9.9(1H) (CD.sub.3                                            OD)                                       5  (63)                                                                                  ##STR77##                                                                            3.9 (92)                                                                             381(M-44) 290                                                                          3400, 1340 1160, 1135                                                                 1.2(3H, C .sub.--H.sub.3) 2.5˜4                                          .5(13H, 6 × C .sub.--H.sub.2 +                                           C .sub.--H) 7.2(5H),                                                           7.5˜9.0(5H) 9.3(1H)                 __________________________________________________________________________

EXAMPLE 10

In 150 ml of ethanol were added 2.77 g of 1-(5-isoquinolinesulfonyl)piperazine, i.e., Compound (35), 1.0 g of potassium hydroxide and 1.9 g of benzyl chloride, and the mixture was refluxed under heating for five hours. After the ethanol was removed from the reaction solution, 100 ml of chloroform was added to the resulting solution, and the solution obtained was washed with a buffer solution having a pH of 5.5 and extracted twice with 20 ml of a 2N aqueous hydrochloric acid solution. The aqueous hydrochloric acid layer was rendered alkaline, extracted twice with 50 ml of chloroform, and the chloroform layer extracted was washed with water and dried with anhydrous magnesium sulfate. After the chloroform was distilled therefrom under reduced pressure, 5 ml of a 10N aqueous hydrochloric acid solution was added to the residue and the mixture was condensed to dryness. The crystalline residue thus obtained was recrystallized from ethanol to give 2.9 g of 1-(5-isoquinolinesulfonyl)-4-benzylpiperazine [i.e., Compound (56)] dihydrochloride in a yield of 66%.

Melting point: 230° C.

Mass spectrum (m/e): 361(M+1), 290(M-C₅ H₁₁), 169 and 98.

NMR spectrum (d⁶ -dimethyl sulfoxide, δ): 3.0˜4.0(8H, 4×NCH₂), 3.3(2H, s, NCH₂), 7.8˜8.8(5H) and 9.3(1H, s).

IR absorption spectrum (ν_(max) ^(KBr) cm⁻¹): 3550, 3450, 1360 and 1165.

EXAMPLE 11

In 50 ml of chloroform were added 2.77 g of 1-(5-isoquinolinesulfonyl)piperazine, i.e., Compound 35 and 1.54 g of anhydrous potassium carbonate, and to the mixture was added dropwise 1.70 g of benzoyl chloride under cooling with ice, and the mixture was stirred at a temperature of 15° C. to 20° C. for three hours. The reaction solution was washed with a 1N aqueous sodium hydroxide solution, then with water and dried with anhydrous magnesium sulfate. After the chloroform was distilled therefrom, the residue thus obtained was subjected to a silica gel column chromatography (silica gel: 70 g; solvent: chloroform) to give 2.7 g of 1-(5-isoquinolinesulfonyl)-4-benzoylpiperazine, i.e., Compound (58) in a yield of 71%.

Melting point (the hydrochloride): 217° C.

Mass spectrum (m/e): 381(M⁺), 318, 276 and 289.

NMR spectrum (CDCl₃, δ): 3.1˜3.9(8H, 4×CH₂), 7.2(5H), 7.5˜8.5(5H) and 9.3(1H).

IR absorption spectrum (ν_(max),^(cap) cm⁻¹): 1690, 1370 and 1160.

The same procedures as described above were repeated using the compounds of the formula, R₆ -W under the reaction conditions as set forth in Table 6-1, and there were obtained 1-(5-isoquinolinesulfonyl)-4-cinnamoylpiperazine, i.e., Compound (60) and 1-(5-isoquinolinesulfonyl)-4-furoylpiperazine, i.e., Compound (61). The results and the analytical values of these compounds are shown in Table 6-2.

                                      TABLE 6-1                                    __________________________________________________________________________      No.Run                                                                            ##STR78##  (g)R.sub.6W     (g)K.sub.2 CO.sub.3                                                                (°C.)TemperatureReaction                                                       (hour)TimeReaction                   __________________________________________________________________________     1  2.77                                                                                       ##STR79##   2.0                                                                               1.54                                                                               15˜20                                                                           3                                     2  "                                                                                          ##STR80##   1.58                                                                              "   "      "                                     __________________________________________________________________________

                                      TABLE 6-2                                    __________________________________________________________________________               ##STR81##         Mass                                                                                AbsorptionIR                                  Run                                                                               Compound          Yield Spectrum                                                                            Spectrum                                                                              NMR Spectrum                            No.                                                                               No.   R.sub.6     [g(%)]                                                                               (m/e)                                                                               (ν.sup.cap .sub.max,                                                               (CDCl.sub.3)                            __________________________________________________________________________     1  60                                                                                    ##STR82##  3.26 (80)                                                                            407, 344 277, 215                                                                   3400, 1645 1600, 1360 1165                                                            3.2˜3.8(8H, 4 × C                                                  .sub.--H.sub.2) 6.7˜7.5(2H,                                              2 × C .sub.--H) 7.3(5H),                                                 7.9˜9.2(5H) 10.0(1H)              2  61                                                                                    ##STR83##  3.26 (88)                                                                            371  3400, 1620 1490, 1335 1170,                                                            3.0˜4.0(8H, 4 × C                                                 .sub.--H.sub.2) 6.4(1H), 6.95(1H)                                              7.4(1H), 7.4˜8.8(5H)              __________________________________________________________________________                                            9.3(1H)                            

EXAMPLE 12

In 30 ml of methylene chloride were dissolved 1.75 g of 2,5-dimethylpiperazine and 1.53 g of triethylamine, and to the solution was added dropwise 20 ml of a methylene chloride solution containing 1.73 g of 5-isoquinolinesulfonyl chloride under cooling with ice. After the dropwise addition of the methylene chloride solution, the mixed solution obtained was stirred at a temperature of 5° C. to 10° C. for three hours, and then the reaction mixture solution was washed with water and dried with anhydrous magnesium sulfate. After the methylene chloride was distilled therefrom, the residue obtained was subjected to an alumina column chromatography (alumina: 50 g; solvent: chloroform) to give 1.38 g of 1-(5-isoquinolinesulfonyl)-2,5-dimethylpiperazine, Compound (40) in a yield of 59%.

Mass spectrum (m/e): 305, 277, 249, 192 and 128.

NMR spectrum (CDCl₃): 0.8˜1.3(6H, 2×CH₃), 1.7(1H, NH), 2.3˜4.2 (6H, 2×CH₂ +×CH), 7.6(1H), 8.0˜8.8(4H) and 9.3(1H).

The same procedures as described above were repeated using the compounds of Formula (III) as set forth in Table 7-1 under the reaction conditions as set forth in Table 7-1, and there were obtained 1-(5-isoquinolinesulfonyl)-3-methylpiperazine, i.e., Compound (37); 1-(5-isoquinolinesulfonyl)-3,5-dimethylpiperazine, i.e., Compound (39); 1-(5-isoquinolinesulfonyl)-2,3-dimethylpiperazine, i.e., Compound (41); 1-(5-isoquinolinesulfonyl)-3-ethylpiperazine, i.e., Compound (43); 1-(5-isoquinolinesulfonyl)-3-isopropylpiperazine, i.e., Compound (45); 1-(5-isoquinolinesulfonyl)-3-isobutylpiperazine, i.e., Compound (46); 1-(5-isoquinolinesulfonyl)-2,5-diethylpiperazine, i.e., Compound (48); 1-(5-isoquinolinesulfonyl)-2-methyl-5-isobutylpiperazine, i.e., Compound (49); 1-(5-isoquinolinesulfonyl)-2-methyl-5-benzylpiperazine, i.e., Compound (50); 1-(5-isoquinolinesulfonyl)-3-phenylpiperazine, i.e., Compound (53); 1-(5-isoquinolinesulfonyl)-3-benzylpiperazine, i.e., Compound (54); and 1-(5-isoquinolinesulfonyl)-3,3-dimethylpiperazine, i.e., Compound (68). The results and the analytical values of these compounds are shown in Table 7-2.

                                      TABLE 7-1                                    __________________________________________________________________________      No.Run                                                                            ##STR84##                                                                                 ##STR85##     (g)N(C.sub.2 H.sub.5).sub.3                                                         (°C.)TemperatureReaction                                                       (hour)TimeReaction                    __________________________________________________________________________     1  1.73                                                                                       ##STR86## 1.52                                                                              1.53  2˜10                                                                            2                                     2  "                                                                                          ##STR87## 1.73                                                                              "    "      "                                      3  1.0                                                                                        ##STR88## 1.25                                                                              1.1  15˜25                                                                            1                                     4  1.14                                                                                       ##STR89## 1.14                                                                              1.0  "      10                                     5  "                                                                                          ##STR90## 1.28                                                                              "    "      18                                     6  "                                                                                          ##STR91## 1.42                                                                              "    "      "                                      7  1.73                                                                                       ##STR92## 2.28                                                                              1.53 "      "                                      8  1.0                                                                                        ##STR93## 3.43                                                                              2.3  38     20                                     9  "                                                                                          ##STR94## 4.17                                                                              "    "      "                                      10 "                                                                                          ##STR95## 3.56                                                                              "    "      "                                      11 "                                                                                          ##STR96## 3.90                                                                              "    "      "                                      12 1.14                                                                                       ##STR97## 1.14                                                                              1.0  15˜25                                                                           "                                      __________________________________________________________________________

                                      TABLE 7-2                                    __________________________________________________________________________               ##STR98##                                                             No.Run                                                                            No.Compound                                                                          ##STR99##     [g(%)]Yield                                                                         (m/e)SpectrumMass                                                                   (ν.sup.cap .sub.max,                                                       cm.sup.-1)SpectrumAbsorptionIR                                                         (CDCl.sub.3)NMR                       __________________________________________________________________________                                             Spectrum                               1  (37)                                                                                  ##STR100##   1.60 (88)                                                                           276, 206 162, 148                                                                   3300, 3000 2950, 2850 1610, 1560 1480,                                         1360 1330, 1160 1140, 1070 1040                                                       0.95(3H, C .sub.--H.sub.3),                                                    1.6(1H, N .sub.--H) 1.8˜3.2(                                             5H), 3.65(2H) 7.6(1H),                                                         8.1˜8.7(4H) 9.3(1H)              2  (39)                                                                                  ##STR101##   2.14 (92)                                                                           305, 278 264, 249 192, 128 114                                                      3350, 2920 2850, 1450 1370, 1330 1155,                                         1140   1.0(6H, 2 × C .sub.--H.sub.3                                             ), 2.1(2H) 2.5˜3.3(2H),                                                  3.6˜4.0(2H) 4.3(1H, N                                                    .sub.--H), 7.8(1H) 8.1˜8.8(4                                             H), 9.4(1H)                            3  (41)                                                                                  ##STR102##   1.0  (75)                                                                           305, 277 249, 192 128                                                               3400, 2920 2850, 1610 1360, 1330 1160,                                         1140   0.9˜1.3(6H, 2 × C                                                  .sub.--H.sub.3) 1.6(1H, N                                                      .sub.--H), 2.6˜4.3(6H)                                                   7.6(1H), 8.1˜8.8(4H)                                                     9.3(1H)                                4  (43)                                                                                  ##STR103##   1.07 (70)                                                                           305, 206 192, 128 114                                                               3400, 2950 2800, 1600 1360, 1340 1160,                                         1140   1.0(3H, C .sub.--H.sub.3),                                                     1.4(2H) 2.1(1H, N .sub.--H),                                                   1.8˜3.0(5H) 3.6(2H),                                                     7.6(1H) 8.0˜8.6(4H),                                                     9.3(1H)                                5  (45)                                                                                  ##STR104##   1.02 (64)                                                                           319, 276 221, 128                                                                   3400, 1610 1480, 1370 1335, 1160                                                      0.7˜1.3(7H, C.sub.3                                                      .sub.--.sub.7), 2.1(1H, N                                                      .sub.--H) 1.8˜3.5(5H),                                                   3.7(2H) 7.6(1H),                                                               8.1˜8.8(4H) 9.3(1H)              6  (46)                                                                                  ##STR105##   1.07 (64)                                                                           333, 221 128                                                                        3350, 1600 1470, 1360 1330, 1160                                                      0.5˜1.3(9H, C.sub.4                                                      .sub.--.sub. 9), 2.7(1H, N                                                     .sub.--) 2.0˜3.4(5H),                                                    3.75(2H) 7.5(1H),                                                              8.1˜8.7(4H), 9.3(1H)             7  (48)                                                                                  ##STR106##   1.65 (65)                                                                           333, 265 248, 192                                                                   3400, 1610 1400, 1360 1340, 1160                                                      0.7˜1.8(10H, 2 ×                                                   C.sub.2  .sub.--H.sub.5), 1.7(1H)                                              .3˜4.3(6H), 7.6(1H)                                                      8.0˜8.7(4H), 9.3(1H)             8  (49)                                                                                  ##STR107##   0.88 (58)                                                                           347, 220 192, 128                                                                   3400, 1610 1450, 1360 1340, 1160                                                      0.7˜1.8(12H, C.sub.4                                                     .sub.--H.sub.9 + C .sub.--H.sub.3)                                              1.8(1H), 2.0˜4.1(6H),                                                   7.7(1H) 8.1˜8.8(4H),                                                     9.3(1H)                                9  (50)                                                                                  ##STR108##   1.25 (75)                                                                           381, 291 220, 128                                                                   3350, 1600 1500, 1355 1340, 1160                                                      1.0(3H, C .sub.--H.sub.3),                                                     1.6(1H, N .sub.--H) 2.0˜4.3(                                             8H), 7.1(5H) 7.6(1H),                                                          8.0˜8.6(4H) 9.3(1H)              10 (53)                                                                                  ##STR109##   1.23 (79)                                                                           353, 312 278, 235 192, 167                                                          3300, 1600 1510, 1360 1335, 1160                                                      1.6(1H), 1.8˜3.2(5H)                                                     3.65(2H), 7.2(5H) 7.6(1H),                                                     8.1˜8.7(4H) 9.3(1H)              11 (54)                                                                                  ##STR110##   1.13 (70)                                                                           367, 276 220, 148 128                                                               3400, 1600 1500, 1360 1340, 1160                                                      1.0˜1.5(2H), 1.9(1H)                                                     1.9˜3.2(5H), 3.7(2H)                                                     7.2(5H), 7.6(1H) 8.1˜8.7(4H)                                             , 9.3(1H)                              12 (68)                                                                                  ##STR111##   0.96 (63)                                                                           305, 290 276, 191 129                                                               3300, 3000 2950, 1620 1560, 1370 1160,                                         1140   1.2(6H, 2 × C .sub.--H.sub.3                                             ), 1.3˜2.1(1H, N .sub.--H)                                               2.6˜3.4(6H, 3 × C                                                  .sub.--H.sub.2),                                                               7.6(1H) 8.0˜8.7(4H),             __________________________________________________________________________                                             9.3(1H)                           

EXAMPLE 13

In 50 ml of chloroform were dissolved 4.68 g of 1-benzyloxycarbonyl-3-methylpiperazine and 1.01 g of triethylamine, and to the solution was added dropwise 20 ml of a chloroform solution containing 4.55 g of 5-isoquinolinesulfonyl chloride, and the mixed solution was stirred at a temperature of 20° C. to 25° C. for 20 hours. The reaction solution obtained was washed with a saturated aqueous sodium hydrogencarbonate solution then with a saturated aqueous ammonium chloride solution, dried with anhydrous magnesium sulfate and concentrated to dryness under reduced pressure to 8.1 g of 1-(5-isoquinolinesulfonyl)-4-benzyloxycarbonyl-2-methylpiperazine as a yellowish white oily substance.

NMR spectrum (CDCl₃): 1.0(3H, d, CH₃), 2.5˜4.3(7H), 5.0(2H, S, ##STR112## 7.25(5H, S, C₆ H₅), 7.55(1H), 8.0˜8.7(4H) and 9.2(1H).

IR absorption spectrum (ν_(max),^(cap) cm⁻¹): 1700, 1360 and 1130.

To 1.65 g of 1-(5-isoquinolinesulfonyl)-4-benzyloxycarbonyl-2-methylpiperazine as obtained above was added 5 ml of 25% hydrobromic acid-acetic acid, and the mixture was stirred at 20° C. for five hours. To the reaction solution was added 30 ml of ethyl ether, and the crystals precipitated were separated by filtration. The crystals thus obtained were dissolved in 20 ml of water and washed with chloroform. Then the pH of the aqueous layer was adjusted to 9 with a 1N aqueous sodium hydroxide solution, extracted with chloroform, and the chloroform layer was washed with water and dried with anhydrous magnesium sulfate. Then the chloroform was distilled therefrom under reduced pressure to give 1.05 g of 1-(5-isoquinolinesulfonyl)-2-methylpiperazine, i.e., Compound (38) in a yield of 93%.

Mass spectrum (m/e): 291, 277, 249, 192, 129 and 128.

NMR spectrum (CDCl₃): 1.3(6H, d, 2×CH₃), 1.9(1H, NH), 2.2˜3.1(4H), 3.1˜4.0(2H), 4.2(1H), 7.7(1H), 8.1˜8.8(4H) and 9.3(1H).

IR spectrum (ν_(max),^(cap) cm⁻¹): 3330, 2940, 2870, 2830, 1607, 1370, 1320, 1160, 1135, 990 and 760.

EXAMPLE 14

In 40 ml of chloroform were dissolved 2.23 g of 2-benzyloxycarbonyl-1-methylethylamine and 1.2 g of triethylamine, and to the solution was added dropwise 20 ml of a chloroform solution containing 2.28 g of 5-isoquinolinesulfonyl chloride under cooling with ice. After the dropwise addition of the chloroform solution, the mixed solution was stirred at a temperature of 20° C. to 25° C. for two hours. The reaction solution obtained was washed with a saturated aqueous hydrogencarbonate solution, then with water, dried with anhydrous magnesium sulfate and then the chloroform was distilled therefrom under reduced pressure to give 3.55 g of N-(2-benzyloxycarbonylamino-1-methylethyl)-5-isoquinolinesulfonamide in a yield of 89%.

NMR spectrum (CDCl₃): 0.95(3H, CH₃), 2.5˜4.5(3H), 5.0(2H, ##STR113## 6.6(1H), 7.2(5H), 7.6(1H), 8.0˜8.6(4H) and 9.3(1H).

IR absorption spectrum (ν_(max),^(cap) cm⁻¹): 3350, 1700, 1330 and 1160.

To 2.0 g of N-(2-benzyloxycarbonylamino-1-methylethyl)-5-isoquinolinesulfonamide as obtained above was added 5 ml of 25% hydrobromic acid-acetic acid, and the mixture was stirred at a temperature of 20° C. to 25° C. for 20 hours. To the reaction solution was added 30 ml of ethyl ether, and the crystals precipitated were separated by filtration. The crystals thus obtained were dissolved in 20 ml of water, washed with chloroform, rendered alkaline with a 1N sodium hydroxide solution and extracted with chloroform. The chloroform layer was washed with water, dried with anhydrous magnesium sulfate and the chloroform was distilled under reduced pressure to give 1.2 g of N-(2-amino-1-methylethyl)-5-isoquinolinesulfonamide, i.e., Compound (6) in a yield of 90%.

Mass spectrum (m/e): 265, 240, 221, 192 and 128.

NMR spectrum (CDCl₃): 1.1(3H), 1.7(2H), 2.6(2H), 3.7(1H), 6.5(1H), 7.6(1H), 8.0˜8.7(4H) and 9.3(1H).

IR absorption spectrum (ν_(max),^(cap) cm⁻¹): 3400, 2900, 1610, 1460, 1330, 1160 and 1140.

The same procedures as described above were repeated using the compounds of Formula (III) as set forth in Table 8-1 under the reaction conditions as set forth in Table 8-1 and Table 8-2, and there were obtained N-(1-aminomethylpropyl)-5-isoquinolinesulfonamide, i.e., Compound (7); N-(1-aminomethylpentyl)-5-isoquinolinesulfonamide, i.e., Compound (8); and N-(2-amino-1-phenylethyl)-5-isoquinolinesulfonamide, i.e., Compound (12). The analytical values of these compounds thus obtained are shown in Table 8-3.

                                      TABLE 8-1                                    __________________________________________________________________________                                               ##STR114##                            Run                                                                               ##STR115##                                                                                ##STR116##                                                                               N(C.sub.2 H.sub.5).sub.3                                                            TemperatureReaction                                                                   TimeReaction                                                                        Yield                                                                                SpectrumIR Absorption          No.                                                                               (g)        R.sub.1                                                                               (g)                                                                               (g)  (°C.)                                                                          (hour)                                                                              [g (%)]                                                                              (ν.sup.cap .sub.max,                                                        cm.sup.-1)                      __________________________________________________________________________     1-1                                                                               2.28       C.sub.2 H.sub.5                                                                       2.4                                                                               1.2  20˜25                                                                           4    3.5                                                                               (85)                                                                              1710, 1330, 1160                2-1                                                                               "          n-C.sub.4 H.sub.9                                                                     2.8                                                                               "    "      "    3.1                                                                               (70)                                                                              1710, 1340, 1160                3-1                                                                               "                                                                                          ##STR117##                                                                           3.0                                                                               "    "      "    3.4                                                                               (74)                                                                              1710, 1330,                     __________________________________________________________________________                                                    1160                       

                                      TABLE 8-2                                    __________________________________________________________________________      Run                                                                               ##STR118##    25% HBrCH.sub.3 COOH                                                                       TemperatureReaction                                                                   TimeReaction                                                                        Product                                                                                Yield                        No.                                                                               R.sub.1  (g)  (ml)        (°C.)                                                                          (hour)                                                                              Compound No.                                                                           [g (%)]                       __________________________________________________________________________     1-2                                                                               C.sub.2 H.sub.5                                                                         1.5  5           20˜25                                                                           12   (7)     0.90                                                                              (89)                       2-2                                                                               n-C.sub.4 H.sub.9                                                                       "    "           "      "    (8)     0.92                                                                              (88)                       3-2                                                                                ##STR119##                                                                             "    "           "      18   (12)    0.74                                                                              (70)                        ##STR120##                                                                    __________________________________________________________________________

                                      TABLE 8-3                                    __________________________________________________________________________      Run                                                                               Compound                                                                             ##STR121##  SpectrumMass                                                                          SpectrumIR Absorption                                                                  NMR Spectrum                              No.                                                                               No.   R.sub.1     (m/e)  (ν.sup.cap .sub.max, cm.sup.-1)                                                     (CDCl.sub.3)                               __________________________________________________________________________     1  (7)   C.sub.2 H.sub.5                                                                            279, 249, 221                                                                         3400, 2900, 1460                                                                       0.8(3H, C .sub.--H.sub.3),                                                     1.0˜1.7(2H)                                               192, 128                                                                              1360, 1160, 1140                                                                       1.9(2H, N .sub.--H.sub.2),                                                     2.5˜4.0(3H)                                                              6.7(1H), 7.6˜8.8(5H)                                                     9.3(1H)                                    2  (8)   n-C.sub.4 H.sub.9                                                                          307, 277, 221                                                                         3350, 2900, 1370                                                                       0.7˜2.0(9H), 2.1(2H,                                                     N .sub.--H.sub.2)                                               192, 128                                                                              1160, 1130                                                                             2.5˜3.8(3H), 7.0(1H)                                                     7.6˜8.8(5H), 9.3(1H)                 3  (12)                                                                                  ##STR122## 327, 297, 192  128                                                                    3350, 1610, 1350 1160, 1140                                                            1.7(2H, N .sub.--H.sub.2),                                                     2.5-4.4(3H) 6.6(1H),                                                           7.1(5H) 7.7˜8.8(5H),                 __________________________________________________________________________                                         9.3(1H)                               

EXAMPLE 15

In 50 ml of chloroform were dissolved 2.0 g of 2-acetamidopropylamine and 2.6 g of triethylamine, and to the solution was added dropwise 50 ml of a chloroform solution containing 3.28 g of 5-isoquinolinesulfonyl chloride under cooling with ice. Then the mixed solution was stirred at a temperature of 15° C. to 25° C. for two hours, and the reaction solution was washed with water, dried with anhydrous magnesium sulfate and the chloroform was distilled therefrom under reduced pressure to give 3.67 g of N-(2-acetamidopropyl)-5-isoquinolinesulfonamide in a yield of 83%.

NMR spectrum (CDCl₃): 1.0(3H, d, CH₃), 2.2(3H, COCH₃), 2.6˜3.8(3H), 5.5˜7.0(2H), 7.6(1H), 8.0˜8.7(4H) and 9.3(1H).

IR absorption spectrum (ν_(max),^(cap) cm⁻¹) 3300, 1670, 1365, 1150, 1130.

The reaction mixture of 3.0 g of the N-(2-acetamidopropyl)-5-isoquinolinesulfonamide as obtained above and 50 ml of 10% hydrochloric acid was stirred at a temperature of 90° C. to 100° C. for 36 hours. Then the reaction solution was washed with chloroform, rendered alkaline with 1N sodium hydroxide and extracted with chloroform. The chloroform layer was washed with water, dried with anhydrous magnesium sulfate, and the chloroform was distilled therefrom under reduced pressure. The residue thus obtained was subjected to an alumina column chromatography (alumina: 70 g; solvent: chloroform) to give 1.14 g of N-(2-aminopropyl)-5-isoquinolinesulfonamide, i.e., Compound (9) in a yield of 44%.

Mass spectrum (m/e): 265, 222, 193, 129 and 128.

NMR spectrum (CDCl₃): 1.0(3H), 1.7(2H), 2.9˜4.0(3H), 6.8(1H), 7.5(1H), 8.1˜8.6(4H) and 9.3(1H).

IR absorption spectrum (ν_(max),^(cap) cm⁻¹): 3400, 1610, 1460, 1370, 1150 and 1130.

The same procedures as described above were repeated using the compounds of Formula (IV) as set forth in Table 9-1 under the reaction conditions as set forth in Table 9-1 and Table 9-2, and there were obtained N-(2-amino-3-methylbutyl)-5-isoquinolinesulfonamide, i.e., Compound (11) and N-(2-amino-2-phenylethyl)-5-isoquinolinesulfonamide, i.e., Compound (13). The analytical values of these compounds are shown in Table 9-3.

                                      TABLE 9-1                                    __________________________________________________________________________                                                   ##STR123##                        Run                                                                               ##STR124##                                                                                ##STR125##    N(C.sub.2 H.sub.5).sub.3                                                            TemperatureReaction                                                                   TimeReaction                                                                        Yield    SpectrunIR                                                                    Absorption               No.                                                                               (g)        R.sub.1  (g)  (g)  (°C.)                                                                          (hour)                                                                              [g  (%)] (ν.sup.cap                                                                  .sub.max,                __________________________________________________________________________                                                           cm.sup.-1)               1-1                                                                               2.28       i-C.sub.3 H.sub.7                                                                       2.16 1.6  15˜20                                                                           0.5  2.31                                                                               (69) 1665, 1330, 1160         2-1                                                                               "                                                                                          ##STR126##                                                                             2.67 "    "      1    2.77                                                                               (75) 1660, 1330,              __________________________________________________________________________                                                           1160                

                                      TABLE 9-2                                    __________________________________________________________________________      Run                                                                               ##STR127##       10% HCl                                                                             TemperatureReaction                                                                   TimeReaction                                                                        Product                                                                                Yield                            No.                                                                               R.sub.1   (g)    (ml) (°C.)                                                                          (hour)                                                                              Compound No.                                                                           [g (%)]                           __________________________________________________________________________     1-2                                                                               i-C.sub.3 H.sub.7                                                                        1.34   30   100    35   (11)    0.60                                                                              (51)                           2-2                                                                                ##STR128##                                                                              1.11   "    "      30   (13)    0.38                                                                              (39)                            ##STR129##                                                                    __________________________________________________________________________

                                      TABLE 9-3                                    __________________________________________________________________________      Run                                                                               Compound                                                                             ##STR130##  Mass Spectrum                                                                          IR Absorption Spectrum                                                                 NMR Spectrum                             No.                                                                               No.   R.sub.1     (m/e)   (ν.sup.cap .sub.max,  cm.sup.-1)                                                    (CDCl.sub.3)                              __________________________________________________________________________     1  (11)  i-C.sub.3 H.sub.7                                                                           221, 192, 148                                                                         3450, 1600, 1460                                                                       0.9(6H, 2 × C .sub.--H.sub.3),                                           1˜1.8(1H)                                                128     1330, 1160, 1140                                                                       2.5˜3.8(3H), 2.1(2H)                                                     7.6(1H), 8.1˜8.9(4H)                                                     9.3(1H)                                   2  (13)                                                                                  ##STR131## 221, 192, 148 128                                                                      3400, 1610, 1440 1400, 1330,                                                           1.7(2H, N .sub.--H.sub.2),                                                     2.7˜4.0(3H) 6.8(1H), 7.2(5H),                                            7.6(1H) 8.0˜8.8(4H),                __________________________________________________________________________                                          9.3(1H)                              

EXAMPLE 16

In 70 ml of methylene chloride were dissolved 3.24 g of 2-(N-methyl-N-benzylamino)ethylamine and 2.0 g of triethylamine, and to the solution was added dropwise 50 ml of a methylene chloride solution containing 3.0 g of 5-isoquinolinesulfonyl chloride under cooling with ice. After the dropwise addition of the methylene chloride solution, the mixed solution was stirred at a temperature of 15° C. to 25° C. for one hour, and then the reaction solution was washed with water and extracted with a 10% aqueous hydrochloric acid solution. The aqueous layer was washed with chloroform, rendered alkaline with a 1N aqueous sodium hydroxide solution, extracted with chloroform, and then the chloroform layer was washed with water, dried with anhydrous magnesium sulfate and the chloroform was distilled therefrom under reduced pressure. The residue thus obtained was subjected to a silica gel column chromatography (silica gel: 100 g; solvent: chloroform) to give 3.84 g of N-[2-(N-methyl-N-benzylamino)ethyl]-5-isoquinolinesulfonamide, i.e., Compound (65) in a yield of 84%.

Mass spectrum (m/e): 355, 340, 264, 221 and 128.

NMR spectrum (CDCl₃): 1.9(3H, NCH₃), 2.3˜2.7(2H), 3.0˜3.3(2H), 3.5(2H, ##STR132## 6.8(1H), 7.2(5H), 7.6(1H), 8.0˜8.5(4H) and 9.3(1H).

IR absorption spectrum (ν_(max),^(cap) cm⁻¹): 3050, 2950, 1620, 1450, 1330, 1155 and 1135.

The same procedures as described above were repeated using the compound of Formula (III) as set forth in Table 10-1 under the reaction conditions as set forth in Table 10-1, and there was obtained N-[2-(N-isopropyl-N-benzylamino)ethyl]-5-isoquinolinesulfonamide, i.e., Compound (67). The analytical values of this compound are shown in Table 10-2.

                                      TABLE 10-1                                   __________________________________________________________________________      ##STR133##                                                                                ##STR134##   N(C.sub.2 H.sub.5).sub.3                                                            Reaction Temperature                                                                  Reaction Time                                                                       Product Compound (67) Yield          (g)        (g)          (g)  (°C.)                                                                          (hour)                                                                              [g(%)]                                __________________________________________________________________________     4.55       3.84         2.2  15˜25                                                                           1    5.44                                                                               (71)                              __________________________________________________________________________

                                      TABLE 10-2                                   __________________________________________________________________________                                 IR Absorption                                      Product             Mass Spectrum                                                                          Spectrum                                           Compound (67)       (m/e)   (ν.sup.cap .sub.max,  cm.sup.-1)                                                    NMR Spectrum (CDCl.sub.3)                  __________________________________________________________________________      ##STR135##         383, 340 221, 128                                                                      2950, 1610, 1450 1335, 1160,                                                            ##STR136##                                __________________________________________________________________________

EXAMPLE 17

In 100 ml of ethanol was dissolved 2.0 g of N-[2-(N-methyl-N-benzylamino)ethyl]-5-isoquinolinesulfonamide, i.e., Compound (65) as obtained in Example 16, and to the solution was added 0.2 g of 10% palladium-carbon. Then the solution was vigorously stirred at a temperature of 20° C. to 25° C. in a hydrogen stream of 2.0 to 2.5 atm. for 5 hours. After the palladium-carbon was separated from the reaction solution by filtration, the reaction solution was concentrated to dryness to give 0.95 g of N-(2-methylaminoethyl)-5-isoquinolinesulfonamide, i.e., Compound (14) in a yield of 64%.

Mass spectrum (m/e): 265, 250, 221 and 128.

NMR spectrum (CDCl₃): 1.7(1H, NH), 2.9(3H, CH₃), 2.5˜3.1(2H), 3.1˜3.5(2H), 7.0(1H), 7.6(1H), 8.1˜8.5(4H) and 9.3(1H).

IR absorption spectrum (ν_(max),^(cap) cm⁻¹): 3400, 1610, 1350, 1330, 1160 and 1140.

The same procedures as described above were repeated using Compound (67) under the reaction conditions as set forth in Table 11-1, and there was obtained N-(2-isopropylaminoethyl)-5-isoquinolinesulfonamide, i.e., Compound (16). The analytical values of this compound are shown in Table 11-2.

                                      TABLE 11-1                                   __________________________________________________________________________                                Hydrogen                                                                             Reaction                                                                              Reaction                                                                            Product                           Starting Material   10% PdC                                                                               Pressure                                                                             Temperature                                                                           Time Yield                             (g)                 (g)    (atm.)                                                                               (°C.)                                                                          (hour)                                                                              [g (%)]                           __________________________________________________________________________      ##STR137##         0.15   2     20˜25                                                                           10   0.50                                                                              (44)                           Compound (67)                                                                  __________________________________________________________________________

                                      TABLE 11-2                                   __________________________________________________________________________     Product        Mass Spectrum                                                                          IR Absorption Spectrum                                                                     NMR Spectrum                                Compound (16)  (m/e)   (ν.sup.cap .sub.max, cm.sup.-1)                                                         (CDCl.sub.3)                                __________________________________________________________________________      ##STR138##    293, 263, 221 143, 128                                                                 3400, 1600, 1350, 1330 1160, 1140                                                          1.0(6H, 2 × C .sub.--H.sub.3),                                           2.1(1H, N .sub.--H) 2.5˜2.9(2H),                                         3.0˜3.5(3H) 6.8(1H),                                                     7.6˜8.8(5H), 9.3(1H)                  __________________________________________________________________________

RELAXATION OF MESENTERIC ARTERY

After a home bred rabbit of a Japanese species weighing about 3 Kg was subjected to bloodletting, resulting in death and then to abdominal incision, the mesenteric artery was taken out, cut into helicoids of 2 mm×25 mm and suspended in a 20 ml organ bath filled with a Krebs-Henseleit solution into which a mixed gas of 95% by volume of O₂ and 5% by volume of CO₂ was introduced and one end of the artery was connected with an isometric transducer. When a load of 1.5 g was applied to the artery, the contraction and the relaxation of the artery were recorded as a weight on the transducer (a product of Nippon Koden K.K., Japan, "FD Pickup TB-912T"). The relaxation of the mesenteric artery was observed by adding the isoquinolinesulfonyl derivatives and their pharmaceutically acceptable acid addition salts of this invention to the mesenteric artery at the condition of about one half of the maximum contraction with KCl at a KCl concentration of 15˜20 mM. When the complete relaxation of the mesenteric artery was designated 100%, the concentration of the isoquinolinesulfonyl derivatives and their pharmaceutically acceptable acid addition salts which brought about a relaxation of 50% is shown in Table 12.

                  TABLE 12                                                         ______________________________________                                                 Relaxation              Relaxation                                             of Mesenteric           of Mesenteric                                  Compound                                                                               Artery ED.sub.50                                                                             Compound  Artery ED.sub.50                               Nos.    (μM)       Nos.      (μM)                                        ______________________________________                                         ( 1)    5             (34)      10                                             ( 2)    7             (35)      0.6                                            ( 3)    11            (36)      7.7                                            ( 4)    10            (37)      4.0                                            ( 5)    14            (38)      5.0                                            ( 6)    10            (39)      9.5                                            ( 7)    21            (40)      0.6                                            ( 8)    19            (41)      1.5                                            ( 9)    15            (42)      18                                             (11)    28            (43)      6.1                                            (12)    18            (44)      8.6                                            (13)    25            (45)      7.5                                            (14)    12            (46)      6.5                                            (16)    10            (47)      24                                             (17)    10            (48)      1.8                                            (18)    30            (49)      10                                             (19)    17            (50)      16                                             (20)    42            (51)      19                                             (21)    50            (53)      7                                              (22)    42            (54)      11                                             (23)    4.0           (55)      9                                              (24)    17            (56)      23                                             (25)    13            (57)      12                                             (26)    8.8           (58)      40                                             (27)    21            (59)      6.8                                            (28)    19            (60)      27                                             (29)    13            (61)      24                                             (30)    8.9           (63)      13                                             (31)    28            (65)      13                                             (32)    16            (67)      18                                             (33)    11                                                                     ______________________________________                                    

EFFECT ON BLOOD FLOW VOLUME OF FEMORAL AND VERTEBRAL ARTERIES OF DOG

The effect on the vasodilatation of the femoral and vertebral arteries was measured by anesthetizing a dog of mixed breed weighing 8 to 15 Kg by an intravenous administration of 35 mg/Kg of pentabarbital, providing an acute type probe (a product of Nippon Koden K.K., Japan) with the femoral and vertebral arteries, administering the 5-isoquinolinesulfonyl derivatives and their pharmaceutically acceptable acid addition salts to the femoral vein through a polyethylene tube inserted into the femoral vein side chain and measuring the blood flow volume with an electromagnetic blood flowmeter (a product of Nippon Koden K.K., Japan, "MF-27"). The results are shown in Table 13.

                  TABLE 13                                                         ______________________________________                                                Amount of   Increased Blood                                                                             Increased Blood                                Com-   Intravenous Flow Volume in                                                                              Flow Volume in                                 pound  Administration                                                                             Femoral Artery                                                                              Vertebral Artery                               Nos.   (mg/Kg)     (%)          (%)                                            ______________________________________                                          1     1           30           45                                              3     1           33           36                                             19     1           25           20                                             25     1           38           29                                             33     1           35           37                                             35     1           69           98                                             36     1           35           63                                             37     1           65           90                                             40     1           50           110                                            46     1           32           55                                             51     1           39           68                                             59     1           25           49                                             ______________________________________                                    

ACUTE TOXICITY

The acute toxicity of the 5-isoquinolinesulfonyl derivatives and their pharmaceutically acceptable acid addition salts were measured by giving male ddY-strain mice an intravenous administration. The results are shown in Table 14.

                  TABLE 14                                                         ______________________________________                                                Compound                                                                               LD.sub.50                                                              Nos.    (mg/Kg)                                                         ______________________________________                                                 1      108                                                                     3       87                                                                    19      180                                                                    25      137                                                                    33      150                                                                    35       29                                                                    36       94                                                                    37       89                                                                    40       42                                                                    46      130                                                                    51      108                                                                    59      145                                                             ______________________________________                                    

While the invention has been described in detail and with reference to specific embodiments thereof, it will be apparent to one skilled in the art that various changes and modifications can be made therein without departing from the spirit and scope thereof. 

What is claimed is:
 1. A compound of Formula (I): ##STR139## wherein l is zero or one;m and n each is zero or an integer of one to nine; m+n is an integer of at least one; R₁ is a hydrogen atom, a C₁₋₁₀ alkyl group, a C₅₋₆ cycloalkyl group or a phenyl group; R₂ and R₃ are independently C₁₋₆ alkylene groups and linked through an oxygen atom to form a 5- to 7-membered hetrocyclic ring with the adjacent nitrogen atom;or the pharmaceutically acceptable acid addition salt thereof.
 2. The compound of claim 1 wherein l is zero; R₂ and R₃ are C₁₋₆ alkylene groups and linked through an oxygen atom to form a 5- or 7-membered heterocyclic ring together with the adjacent nitrogen atom.
 3. The compound of claim 2 wherein R₂ and R₃ form together with the adjacent nitrogen atom a morpholino group.
 4. The compound of claim 1 wherein l is one; m and n each is zero or an integer of one to nine; m+n is an integer of one to nine; R₁ is a hydrogen atom, a C₁₋₆ alkyl or a phenyl group; and R₂ and R₃ are independently C₁₋₆ alkylene groups and linked through an oxygen atom to form a 5- to 7-membered heterocyclic ring together with the adjacent nitrogen atom.
 5. The compound of claim 4 wherein m and n each is zero or an integer of one to nine; m+n is an integer of one to nine; and R₁ is a hydrogen atom.
 6. The compound of claim 4 wherein m and n each is zero or one; m+n is one; and R₁ is a C₁₋₆ alkyl group or a phenyl group.
 7. The compound of claim 4 wherein m and n each is zero or an integer of one to two; m+n is one or two; and R₁ is a hydrogen atom.
 8. The compound of claim 4 wherein m and n each is zero or an integer of one to two; m+n is one or two; and R₂ and R₃ form together with the adjacent nitrogen atom a morpholino group. 